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Sample records for alters intratumoral drug

  1. Alters Intratumoral Drug Distribution and Affects Therapeutic Synergy of Antiangiogenic Organoselenium Compound

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    Youcef M. Rustum

    2010-01-01

    Full Text Available Tumor differentiation enhances morphologic and microvascular heterogeneity fostering hypoxia that retards intratumoral drug delivery, distribution, and compromise therapeutic efficacy. In this study, the influence of tumor biologic heterogeneity on the interaction between cytotoxic chemotherapy and selenium was examined using a panel of human tumor xenografts representing cancers of the head and neck and lung along with tissue microarray analysis of human surgical samples. Tumor differentiation status, microvessel density, interstitial fluid pressure, vascular phenotype, and drug delivery were correlated with the degree of enhancement of chemotherapeutic efficacy by selenium. Marked potentiation of antitumor activity was observed in H69 tumors that exhibited a well-vascularized, poorly differentiated phenotype. In comparison, modulation of chemotherapeutic efficacy by antiangiogenic selenium was generally lower or absent in well-differentiated tumors with multiple avascular hypoxic, differentiated regions. Tumor histomorphologic heterogeneity was found prevalent in the clinical samples studied and represents a primary and critical physiological barrier to chemotherapy.

  2. Synthesis and characterization of drug loaded albumin mesospheres for intratumoral chemotherapy

    Science.gov (United States)

    Freeman, Shema Taian

    Conventional chemotherapy is problematic due to toxic complications. Intratumoral (IT) drug delivery, offers a new, less toxic, potentially more effective treatment concept. The objectives of this research encompassed (1) an investigation of the synthesis of BSA mesospheres (MS) employing genipin (GEN) as a novel crosslinking agent, (2) comparison with glutaraldehyde (GTA) crosslinked mesosphere, (3) a study of process parameters to define conditions for the synthesis of 1-10microm drug loaded mesospheres, and (4) investigation of the drug delivery properties of such mesospheres for IT chemotherapy. Smooth, spherical BSA-MS, crosslinked with glutaraldehyde and genipin, were prepared in a dry particle size range of 1microm to 10microm. It was shown that increasing dispersion stirring rate, crosslinking time and GEN/BSA ratio led to a decrease in particle size and a narrower particle distribution. It was also shown that increasing crosslinking time, GEN/BSA ratio, BSA concentrations, GEN concentration slowed enzymatic degradation. Post-loading and in situ drug loading methods were studied for the incorporation of cyclophosphamide and cisplatin into mesospheres. Maximum post loading of cisplatin was 3.2% (w/w) and 2.6% (w/w) with GEN and with GTA crosslinking. For cyclophosphamide 8.2% (w/w) and 7.1% (w/w) loading was achieved with GEN and GTA respectively. In situ drug loaded MS genipin and glutaraldehyde crosslinked mesospheres were also synthesized with 1.8% (w/w) cisplatin (using GEN) and 1.2% (w/w) (using GTA). Maximum loading of 13.3% (w/w) was achieved for cyclophosphamide in genipin crosslinked mesospheres. The cytotoxicity of in situ loaded genipin and glutaraldehyde crosslinked cisplatin mesospheres was evaluated using a murine Lewis lung model. Both genipin and glutaraldehyde crosslinked BSA-cisplatin mesospheres proved to be cytotoxic during a 48 hour test. Ultimately a standard set of processing parameters (BSA concentration, CAB concentration, GEN

  3. Intratumor chemotherapy in combination with a systemic antimetastatic drug in the treatment of Lewis-lung carcinoma.

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    De-Oliveira, M M; Nakamura, I T; Joussef, A C; Giannotti Filho, O

    1985-01-01

    The effect of an antimetastatic agent plus intratumor chemotherapy was evaluated in mice bearing Lewis-lung carcinoma by measuring survival time and by histological examination. Polymeric flavan-3,4-diol (APF) from avocado seeds, Persea gratissima, administered alone directly into the tumor did not change survival time, although it partially destroyed the primary tumor. However, the drug administered in combination with an antimetastatic, 1,2-bis(3,5-dioxopiperazin-1-yl)ethane (ICRF-154), resulted in an increase in survival time. When 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) was used in place of polymeric flavanadiol as an intralesional drug, a significant increase in survival was also achieved. The effect of each drug alone and of their combination was evaluated by "responder analyses". Animals "cured" by the combination and rechallenged with 2 X 10(6) tumor cells showed that immunization could occur.

  4. Doxorubicin-Loaded QuadraSphere Microspheres: Plasma Pharmacokinetics and Intratumoral Drug Concentration in an Animal Model of Liver Cancer

    International Nuclear Information System (INIS)

    The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.

  5. Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation.

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    Adam D Cohen

    Full Text Available In vivo GITR ligation has previously been shown to augment T-cell-mediated anti-tumor immunity, yet the underlying mechanisms of this activity, particularly its in vivo effects on CD4+ foxp3+ regulatory T cells (Tregs, have not been fully elucidated. In order to translate this immunotherapeutic approach to the clinic it is important gain better understanding of its mechanism(s of action. Utilizing the agonist anti-GITR monoclonal antibody DTA-1, we found that in vivo GITR ligation modulates regulatory T cells (Tregs directly during induction of melanoma tumor immunity. As a monotherapy, DTA-1 induced regression of small established B16 melanoma tumors. Although DTA-1 did not alter systemic Treg frequencies nor abrogate the intrinsic suppressive activity of Tregs within the tumor-draining lymph node, intra-tumor Treg accumulation was significantly impaired. This resulted in a greater Teff:Treg ratio and enhanced tumor-specific CD8+ T-cell activity. The decreased intra-tumor Treg accumulation was due both to impaired infiltration, coupled with DTA-1-induced loss of foxp3 expression in intra-tumor Tregs. Histological analysis of B16 tumors grown in Foxp3-GFP mice showed that the majority of GFP+ cells had lost Foxp3 expression. These "unstable" Tregs were absent in IgG-treated tumors and in DTA-1 treated TDLN, demonstrating a tumor-specific effect. Impairment of Treg infiltration was lost if Tregs were GITR(-/-, and the protective effects of DTA-1 were reduced in reconstituted RAG1(-/- mice if either the Treg or Teff subset were GITR-negative and absent if both were negative. Our results demonstrate that DTA-1 modulates both Teffs and Tregs during effective tumor treatment. The data suggest that DTA-1 prevents intra-tumor Treg accumulation by altering their stability, and as a result of the loss of foxp3 expression, may modify their intra-tumor suppressive capacity. These findings provide further support for the continued development of agonist

  6. Synergistic anti-tumor activity through combinational intratumoral injection of an in-situ injectable drug depot.

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    Kim, Da Yeon; Kwon, Doo Yeon; Kwon, Jin Seon; Park, Ji Hoon; Park, Seung Hun; Oh, Hyun Ju; Kim, Jae Ho; Min, Byoung Hyun; Park, Kinam; Kim, Moon Suk

    2016-04-01

    Here, we describe combinational chemotherapy via intratumoral injection of doxorubicin (Dox) and 5-fluorouracil (Fu) to enhance the efficacy and reduce the toxicity of systemically administered Fu and Dox in cancer patients. As the key concept in this work, mixture formulations of Dox-loaded microcapsules (Dox-M) and Fu-loaded Pluronic(®) hydrogels (Fu-HP) or Fu-loaded diblock copolymer hydrogels (Fu-HC) have been employed as drug depots. The in vitro and in vivo drug depot was designed as a formulation of Dox-M dispersed inside an outer shell of Fu-HP or Fu-HC after injection. The Dox-M/Fu-HP and Dox-M/Fu-HC formulations are free flowing at room temperature, indicating injectability, and formed a structural gelatinous depot in vitro and in vivo at body temperature. The Fu-HP, Fu-HC, Dox-M/Fu-HP, Dox-M/Fu-HC, and Dox-M formulations were easily injected into tumor centers in mice using a needle. Dox-M/Fu-HC produced more significant inhibitory effects against tumor growth than that by Dox-M/Fu-HP, while Fu-HP, Fu-HC and Dox-M had the weakest inhibitory effects of the tested treatments. The in vivo study of Dox and Fu biodistribution showed that high Dox and Fu concentrations were maintained in the target tumor only, while distribution to normal tissues was not observed, indicating that Dox and Fu concentrations below their toxic plasma concentrations should not cause significant systemic toxicity. The Dox-M/Fu-HP and Dox-M/Fu-HC drug depots described in this work showed excellent performance as chemotherapeutic delivery systems. The results reported here indicate that intratumoral injection using combination chemotherapy with Dox-M/Fu-HP or Dox-M/Fu-HC could be of translational research by enhancing the synergistic inhibitory effects of Dox and Fu on tumor growth, while reducing their systemic toxicity in cancer patients. PMID:26874285

  7. Brain tumor chemo-radiotherapy: a study of direct intratumoral perfusion with antineoplastic drugs

    International Nuclear Information System (INIS)

    High grade gliomas are aggressive tumors for which current treatments remain palliative. Radiotherapy efficacy is restricted by the surrounding brain tissue tolerance. One method based on the concomitant use of chemotherapeutic drugs and external photon irradiation has been proposed to improve the treatment outcome. The systemic administration of drugs is not effective in achieving the therapeutic level of drug needed for brain tumor treatment. This is due to the blood brain barrier (BBB) that prevents molecules passing through the vascular endothelium. Recent methods have been developed to circumvent the BBB. Among them, convection-enhanced delivery (CED) relies on the continuous infusion of a fluid containing a therapeutic agent, under a pressure gradient. It permits a homogeneous and controlled drug distribution. The aims of this study were to characterise the CED method, and then to utilize it for glioma treatment in preclinical studies. Several drugs were tested: cisplatin, carbo-platin, oxaliplatin, and iodo-deoxyuridine. Two radiation modalities were evaluated: synchrotron stereotactic radiotherapy (monochromatic beam < 100 keV) and high energy irradiation (6 MV) obtained with a conventional medical linear accelerator. The results obtained reveal that the effectiveness of the combined treatment (platinated drug plus photon irradiation) is highly related to that of the chemotherapy. The data, obtained with the platinated chemotherapy, also show that high-energy X-ray irradiation (6 MV) is as effective as synchrotron X-ray irradiation. The results broaden the applicability of this chemotherapeutic approach to clinical trials. (author)

  8. Co-encapsulation of magnetic Fe3O4 nanoparticles and doxorubicin into biodegradable PLGA nanocarriers for intratumoral drug delivery

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    Jia Y

    2012-03-01

    Full Text Available Yanhui Jia1, Mei Yuan1, Huidong Yuan1, Xinglu Huang2, Xiang Sui1, Xuemei Cui1, Fangqiong Tang2, Jiang Peng1, Jiying Chen1, Shibi Lu1, Wenjing Xu1, Li Zhang1, Quanyi Guo11Institute of Orthopedics, General Hospital of the Chinese People's Liberation Army, Beijing, People's Republic of China; 2Laboratory of Controllable Preparation and Application of Nanomaterials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, People's Republic of ChinaAbstract: In this study, the authors constructed a novel PLGA [poly(D,L-lactic-co-glycolic acid]-based polymeric nanocarrier co-encapsulated with doxorubicin (DOX and magnetic Fe3O4 nanoparticles (MNPs using a single emulsion evaporation method. The DOX-MNPs showed high entrapment efficiency, and they supported a sustained and steady release of DOX. Moreover, the drug release was pH sensitive, with a faster release rate in an acidic environment than in a neutral environment. In vitro, the DOX-MNPs were easily internalized into murine Lewis lung carcinoma cells and they induced apoptosis. In vivo, the DOX-MNPs showed higher antitumor activity than free DOX solution. Furthermore, the antitumor activity of the DOX-MNPs was higher with than without an external magnetic field; they were also associated with smaller tumor volume and a lower metastases incidence rate. This work may provide a new modality for developing an effective drug delivery system.Keywords: antitumor activity, external magnetic field, intratumoral injection, apoptosis, Lewis lung carcinoma

  9. Design and development of a robotized system coupled to µCT imaging for intratumoral drug evaluation in a HCC mouse model.

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    Gaétan Bour

    Full Text Available Hepatocellular carcinoma (HCC is one of the most common cancer related deaths worldwide. One of the main challenges in cancer treatment is drug delivery to target cancer cells specifically. Preclinical evaluation of intratumoral drugs in orthotopic liver cancer mouse models is difficult, as percutaneous injection hardly can be precisely performed manually. In the present study we have characterized a hepatoma model developing a single tumor nodule by implantation of Hep55.1C cells in the liver of syngeneic C57BL/6J mice. Tumor evolution was followed up by µCT imaging, and at the histological and molecular levels. This orthotopic, poorly differentiated mouse HCC model expressing fibrosis, inflammation and cancer markers was used to assess the efficacy of drugs. We took advantage of the high precision of a previously developed robotized system for automated, image-guided intratumoral needle insertion, to administer every week in the tumor of the Hep55.1C mouse model. A significant tumor growth inhibition was observed using our robotized system, whereas manual intraperitoneal administration had no effect, by comparison to untreated control mice.

  10. Intra-tumor distribution of PEGylated liposome upon repeated injection: No possession by prior dose.

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    Nakamura, Hiroyuki; Abu Lila, Amr S; Nishio, Miho; Tanaka, Masao; Ando, Hidenori; Kiwada, Hiroshi; Ishida, Tatsuhiro

    2015-12-28

    Liposomes have proven to be a viable means for the delivery of chemotherapeutic agents to solid tumors. However, significant variability has been detected in their intra-tumor accumulation and distribution, resulting in compromised therapeutic outcomes. We recently examined the intra-tumor accumulation and distribution of weekly sequentially administered oxaliplatin (l-OHP)-containing PEGylated liposomes. In that study, the first and second doses of l-OHP-containing PEGylated liposomes were distributed diversely and broadly within tumor tissues, resulting in a potent anti-tumor efficacy. However, little is known about the mechanism underlying such a diverse and broad liposome distribution. Therefore, in the present study, we investigated the influence of dosage interval on the intra-tumor accumulation and distribution of "empty" PEGylated liposomes. Intra-tumor distribution of sequentially administered "empty" PEGylated liposomes was altered in a dosing interval-dependent manner. In addition, the intra-tumor distribution pattern was closely related to the chronological alteration of tumor blood flow as well as vascular permeability in the growing tumor tissue. These results suggest that the sequential administrations of PEGylated liposomes in well-spaced intervals might allow the distribution to different areas and enhance the total bulk accumulation within tumor tissue, resulting in better therapeutic efficacy of the encapsulated payload. This study may provide useful information for a better design of therapeutic regimens involving multiple administrations of nanocarrier drug delivery systems.

  11. Inertial cavitation to non-invasively trigger and monitor intratumoral release of drug from intravenously delivered liposomes.

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    Graham, Susan M; Carlisle, Robert; Choi, James J; Stevenson, Mark; Shah, Apurva R; Myers, Rachel S; Fisher, Kerry; Peregrino, Miriam-Bazan; Seymour, Len; Coussios, Constantin C

    2014-03-28

    The encapsulation of cytotoxic drugs within liposomes enhances pharmacokinetics and allows passive accumulation within tumors. However, liposomes designed to achieve good stability during the delivery phase often have compromised activity at the target site. This problem of inefficient and unpredictable drug release is compounded by the present lack of low-cost, non-invasive methods to measure such release. Here we show that focused ultrasound, used at pressures similar to those applied during diagnostic ultrasound scanning, can be utilised to both trigger and monitor release of payload from liposomes. Notably, drug release was influenced by liposome composition and the presence of SonoVue® microbubbles, which provided the nuclei for the initiation of an event known as inertial cavitation. In vitro studies demonstrated that liposomes formulated with a high proportion of 1,2 distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) released up to 30% of payload following ultrasound exposure in the presence of SonoVue®, provided that the exposure created sufficient inertial cavitation events, as characterised by violent bubble collapse and the generation of broadband acoustic emissions. In contrast a 'Doxil'-like liposome formulation gave no such triggered release. In pre-clinical studies, ultrasound was used as a non-invasive, targeted stimulus to trigger a 16-fold increase in the level of payload release within tumors following intravenous delivery. The inertial cavitation events driving this release could be measured remotely in real-time and were a reliable predictor of drug release.

  12. Minimal-invasive magnetic heating of tumors does not alter intra-tumoral nanoparticle accumulation, allowing for repeated therapy sessions: an in vivo study in mice

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    Kettering, Melanie; Richter, Heike; Wiekhorst, Frank; Bremer-Streck, Sibylle; Trahms, Lutz; Alois Kaiser, Werner; Hilger, Ingrid

    2011-12-01

    Localized magnetic heating treatments (hyperthermia, thermal ablation) using superparamagnetic iron oxide nanoparticles (MNPs) continue to be an active area of cancer research. For generating the appropriate heat to sufficiently target cell destruction, adequate MNP concentrations need to be accumulated into tumors. Furthermore, the knowledge of MNP bio-distribution after application and additionally after heating is significant, firstly because of the possibility of repeated heating treatments if MNPs remain at the target region and secondly to study potential adverse effects dealing with MNP dilution from the target region over time. In this context, little is known about the behavior of MNPs after intra-tumoral application and magnetic heating. Therefore, the present in vivo study on the bio-distribution of intra-tumorally injected MNPs in mice focused on MNP long term monitoring of pre and post therapy over seven days using multi-channel magnetorelaxometry (MRX). Subsequently, single-channel MRX was adopted to study the bio-distribution of MNPs in internal organs and tumors of sacrificed animals. We found no distinct change of total MNP amounts in vivo during long term monitoring. Most of the MNP amounts remained in the tumors; only a few MNPs were detected in liver and spleen and less than 1% of totally injected MNPs were excreted. Apparently, the application of magnetic heating and the induction of apoptosis did not affect MNP accumulation. Our results indicate that MNP mainly remained within the injection side after magnetic heating over a seven-days-observation and therefore not affecting healthy tissue. As a consequence, localized magnetic heating therapy of tumors might be applied periodically for a better therapeutic outcome.

  13. Intratumoral Pharmacokinetics: Challenges to Nanobiomaterials.

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    Al-Abd, Ahmed M; Al-Abbasi, Fahad A; Torchilin, Vladimir P

    2015-01-01

    Resistance of solid tumors to treatment is significantly attributed to pharmacokinetic reasons at both cellular and multi-cellular levels. Anticancer agent must be bio-available at the site of action in a cytotoxic concentration to exert its proposed activity. Solid tumor tissue is characterized by high density of vascular bed however; the vast majority of these blood vessels are not functioning. The vast majority of solid tumors can be described as poorly perfused with blood; and anticancer agents need to penetrate/distribute avascularly within solid tumor micro-milieu. Classic pharmacokinetic parameters correlate drug status within central compartment (blood) to all perfused body tissues according to their degree of perfusion. Yet, these classic pharmacokinetic parameters cannot fully elucidate the intratumoral drug penetration/distribution status of anticancer drugs due to the great discrepancies in perfusion between normal and solid tumor tissues. Herein, we will discuss the recently proposed pharmacokinetic parameters that might accurately portray the distribution of anticancer agents within solid tumor micro-milieu. In addition, we will present the new challenges attributed to these new pharmacokinetic parameters towards designing nanobiomaterial drug delivery system. PMID:26027565

  14. In Vivo Confocal Fluorescence Imaging of the Intratumor Distribution of the Photosensitizer Mono-l-Aspartylchlorin-e6

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    Soumya Mitra

    2008-05-01

    Full Text Available We present an in vivo fluorescence microscopic evaluation of intratumor distribution of the photosensitizer mono-l-aspartylchlorin-e6 (NPe6 in an intradermal mouse EMT6 tumor model. Although the identification of favorable photophysical and pharmacological properties has led to the development of new photosensitizers in photodynamic therapy, their intratumor distribution kinetics have remained relatively understudied. In this study, we used confocal fluorescence microscopy to follow the transport of NPe6 in vivo after systemic administration through the tail vein. Labeling of vasculature using fluorophore-conjugated anti-CD31 antibodies allows visualization of the uptake of NPe6 in tumor and normal vessels and its partitioning kinetics into the adjacent parenchyma for 3 hours after injection. During the initial 60 minutes after injection, the drug is predominantly confined to the vasculature. Subsequently, it significantly redistributes throughout the extravascular regions with no discernable difference in its extravasation rate between tumor and normal tissues. Further, we investigate the sensitizer’s altered intratumor distribution in response to photodynamic therapy irradiation and observe that treatment-induced changes in vessel permeability caused enhanced accumulation of NPe6 in the extravascular space. Our findings are of immediate clinical relevance and demonstrate the importance of an in vivo imaging approach to examine the dynamic process of intratumor drug distribution.

  15. Alteration of sensitivity of intratumor quiescent and total cells to γ-rays following thermal neutron irradiation with or without 10B-compound

    International Nuclear Information System (INIS)

    Purpose: Changes in the sensitivity of intratumor quiescent (Q) and total cells to γ-rays following thermal neutron irradiation with or without 10B-compound were examined. Methods and Materials: 5-Bromo-2'-deoxyuridine (BrdU) was injected to SCC VII tumor-bearing mice intraperitoneally 10 times to label all the proliferating (P) tumor cells. As priming irradiation, thermal neutrons alone or thermal neutrons with 10B-labeled sodium borocaptate (BSH) or dl-p-boronophenylalanine (BPA) were administered. The tumor-bearing mice then received a series of γ-ray radiation doses, 0 through 24 h after the priming irradiation. During this period, no BrdU was administered. Immediately after the second irradiation, the tumors were excised, minced, and trypsinized. Following incubation of tumor cells with cytokinesis blocker, the micronucleus (MN) frequency in cells without BrdU labeling (= Q cells at the time of priming irradiation) was determined using immunofluorescence staining for BrdU. The MN frequency in the total (P + Q) tumor cells was determined from the tumors that were not pretreated with BrdU before the priming irradiation. To determine the BrdU-labeled cell ratios in the tumors at the time of the second irradiation, each group also included mice that were continuously administered BrdU until just before the second irradiation using mini-osmotic pumps which had been implanted subcutaneously 5 days before the priming irradiation. Results: In total cells, during the interval between the two irradiations, the tumor sensitivity to γ-rays relative to that immediately after priming irradiation decreased with the priming irradiation ranking in the following order: thermal neutrons only > thermal neutrons with BSH > thermal neutrons with BPA. In contrast, in Q cells, during that time the sensitivity increased in the following order: thermal neutrons only 10B-compound, especially BPA, in thermal neutron irradiation causes the recruitment from the Q to P population

  16. Targeting intratumoral androgens: statins and beyond.

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    Schweizer, Michael T; Yu, Evan Y

    2016-09-01

    While initially effective, androgen deprivation therapy (ADT) is not curative, and nearly all men with advanced prostate cancer will eventually progress to the more resistant, and ultimately lethal form of the disease, so called castration-resistant prostate cancer (CRPC). The maintenance of androgens within the prostate cancer microenvironment likely represents one of the key mechanisms by which this transition from hormone-sensitive to CRPC occurs. This can be accomplished either through intratumoral androgen biosynthesis or the active transport of androgens and androgenic precursors into the tumor microenvironment. More recently, preclinical and clinical data supported therapeutic strategies that seek to target these two mechanisms, either through the use of drugs that impair androgen biosynthesis (e.g. inhibiting the steroidogenic enzymes CYP17 and AKR1C3 with abiraterone and indomethacin, respectively) or drugs that inhibit the SLCO transporters responsible for importing androgens (e.g. statins). PMID:27583031

  17. Drugs that alter biodistribution and kinetics of radiopharmaceuticals

    International Nuclear Information System (INIS)

    Target localization and organ biodistribution of radiopharmaceuticals (RPs) may be altered by non-radioactive drugs whose pharmacological mechanisms compete with the RPs for the same retention processes. Originally referred to as side effects or incompatibilities, such interactions became a major concern in evaluating Nuclear Medicine procedures, as they might cause interpretation of the latter to be without value or misleading. With accumulated experience, some interactions were intentionally included in Nuclear Medicine procedures and became an additional tool in differential diagnosis. Moreover, due to the ability of some RPs to compete with therapeutic agents, Nuclear Medicine studies shifted from anatomical-physiological to more pharmacologically-pathologically-based procedures that can also monitor the stage of disease, and follow its treatment. The aim of this review, therefore, is not only to illustrate some crucial pharmacological issues in Nuclear Medicine imaging, but to emphasize the possible input that alterations of RP biodistribution by drugs may have in achieving better and safer diagnosis, disease staging and monitoring of the patient's response to therapy. 166 references

  18. Oral drug delivery systems comprising altered geometric configurations for controlled drug delivery.

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    Moodley, Kovanya; Pillay, Viness; Choonara, Yahya E; du Toit, Lisa C; Ndesendo, Valence M K; Kumar, Pradeep; Cooppan, Shivaan; Bawa, Priya

    2012-01-01

    Recent pharmaceutical research has focused on controlled drug delivery having an advantage over conventional methods. Adequate controlled plasma drug levels, reduced side effects as well as improved patient compliance are some of the benefits that these systems may offer. Controlled delivery systems that can provide zero-order drug delivery have the potential for maximizing efficacy while minimizing dose frequency and toxicity. Thus, zero-order drug release is ideal in a large area of drug delivery which has therefore led to the development of various technologies with such drug release patterns. Systems such as multilayered tablets and other geometrically altered devices have been created to perform this function. One of the principles of multilayered tablets involves creating a constant surface area for release. Polymeric materials play an important role in the functioning of these systems. Technologies developed to date include among others: Geomatrix(®) multilayered tablets, which utilizes specific polymers that may act as barriers to control drug release; Procise(®), which has a core with an aperture that can be modified to achieve various types of drug release; core-in-cup tablets, where the core matrix is coated on one surface while the circumference forms a cup around it; donut-shaped devices, which possess a centrally-placed aperture hole and Dome Matrix(®) as well as "release modules assemblage", which can offer alternating drug release patterns. This review discusses the novel altered geometric system technologies that have been developed to provide controlled drug release, also focusing on polymers that have been employed in such developments. PMID:22312236

  19. Intestinal Oxidative State Can Alter Nutrient and Drug Bioavailability

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    Faria Ana

    2009-01-01

    Full Text Available Organic cations (OCs are substances of endogenous (e.g., dopamine, choline or exogenous (e.g., drugs like cimetidine origin that are positively charged at physiological ph. since many of these compounds can not pass the cell membrane freely, their transport in or out of cells must be mediated by specific transport systems. Transport by organic cation transporters (OCTs can be regulated rapidly by altering their trafficking and/or affinities in response to stimuli. However, for example, a specific disease could lead to modifications in the expression of OCTs. Chronic exposure to oxidative stress has been suggested to alter regulation and functional activity of proteins through several pathways. According to results from a previous work, oxidation-reduction pathways were thought to be involved in intestinal organic cation uptake modulation. The present work was performed in order to evaluate the influence of oxidative stressors, especially glutathione, on the intestinal organic cation absorption. For this purpose, the effect of compounds with different redox potential (glutathione, an endogenous antioxidant, and procyanidins, diet antioxidants was assessed on MPP+ (1-methyl-4-phenylpyridinium iodide uptake in an enterocyte cell line (Caco-2. Caco-2 cells were subcultured with two different media conditions (physiological: 5 mM glucose, referred as control cells; and high-glucose: 25 mM glucose, referred as HG cells. In HG cells, the uptake was significantly lower than in control cells. Redox changing interventions affected Mpp+ uptake, both in control and in high-glucose Caco-2 cells. Cellular glutathione levels could have an important impact on membrane transporter activity. The results indicate that modifications in the cellular oxidative state modulate MPP+ uptake by Caco-2 cells. Such modifications may reflect in changes of nutrient and drug bioavailability.

  20. HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition.

    Science.gov (United States)

    Kis, Olena; Sankaran-Walters, Sumathi; Hoque, M Tozammel; Walmsley, Sharon L; Dandekar, Satya; Bendayan, Reina

    2016-05-01

    This study investigated the effects of HIV-1 infection and antiretroviral therapy (ART) on the expression of intestinal drug efflux transporters, i.e., P-glycoprotein (Pgp), multidrug resistance-associated proteins (MRPs), and breast cancer resistance protein (BCRP), and metabolic enzymes, such as cytochrome P450s (CYPs), in the human upper intestinal tract. Intestinal biopsy specimens were obtained from HIV-negative healthy volunteers, ART-naive HIV-positive (HIV(+)) subjects, and HIV(+) subjects receiving ART (10 in each group). Intestinal tissue expression of drug transporters and metabolic enzymes was examined by microarray, real-time quantitative reverse transcription-PCR (qPCR), and immunohistochemistry analyses. Microarray analysis demonstrated significantly lower expression of CYP3A4 and ABCC2/MRP2 in the HIV(+) ART-naive group than in uninfected subjects. qPCR analysis confirmed significantly lower expression of ABCC2/MRP2 in ART-naive subjects than in the control group, while CYP3A4 and ABCG2/BCRP showed a trend toward decreased expression. Protein expression of MRP2 and BCRP was also significantly lower in the HIV(+) naive group than in the control group and was partially restored to baseline levels in HIV(+) subjects receiving ART. In contrast, gene and protein expression of ABCB1/Pgp was significantly increased in HIV(+) subjects on ART relative to HIV(+) ART-naive subjects. These data demonstrate that the expression of drug-metabolizing enzymes and efflux transporters is significantly altered in therapy-naive HIV(+) subjects and in those receiving ART. Since CYP3A4, Pgp, MRPs, and BCRP metabolize or transport many antiretroviral drugs, their altered expression with HIV infection may negatively impact drug pharmacokinetics in HIV(+) subjects. This has clinical implications when using data from healthy volunteers to guide ART. PMID:26902756

  1. Ultra-structural hair alterations of drug abusers: a scanning electron microscopic investigation.

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    Turkmenoglu, Fatma Pinar; Kasirga, Ugur Baran; Celik, Hakan Hamdi

    2015-01-01

    As drug abuse carries a societal stigma, patients do not often report their history of drug abuse to the healthcare providers. However, drug abuse is highly co-morbid with a host of other health problems such as psychiatric disorders and skin diseases, and majority of individuals with drug use disorders seek treatment in the first place for other problems. Therefore, it is very important for physicians to be aware of clinical signs and symptoms of drug use. Recently diagnostic value of dermatologic tissue alterations associated with drug abuse has become a very particular interest because skin changes were reported to be the earliest noticeable consequence of drug abuse prompting earlier intervention and treatment. Although hair is an annex of skin, alterations on hair structure due to drug use have not been demonstrated. This study represents the first report on ultra-structural hair alterations of drug abusers. We have investigated ultra-structure of the hair samples obtained from 6 cocaine, 6 heroin, 7 cannabis and 4 lysergic acid diethylamide (LSD) abusers by scanning electron microscope (SEM). SEM analysis of hair samples gave us drug-specific discriminating alterations. We suggest that results of this study will make a noteworthy contribution to cutaneous alterations associated with drug abuse which are regarded as the earliest clinical manifestations, and this SEM approach is a very specific and effective tool in the detection of abuse of respective drugs, leading early treatment. PMID:26309532

  2. Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer

    DEFF Research Database (Denmark)

    Brocks, David; Assenov, Yassen; Minner, Sarah;

    2014-01-01

    Despite much evidence on epigenetic abnormalities in cancer, it is currently unclear to what extent epigenetic alterations can be associated with tumors' clonal genetic origins. Here, we show that the prostate intratumor heterogeneity in DNA methylation and copy-number patterns can be explained b...

  3. Nutritional Alterations in Drug Abusers With and Without HIV

    Directory of Open Access Journals (Sweden)

    Janet E. Forrester

    2006-01-01

    Full Text Available Many studies have found that drug abusers have nutritional deficits, including weight deficits. The most plausible explanation for these deficits is dietary insufficiency. However, studies using objective measures of the dietary intake of drug abusers have failed to provide evidence of dietary insufficiency. Other mechanisms have rarely been examined. This article reviews the published literature on the nutritional status of drug abusers with and without HIV, with emphasis on dietary energy and macronutrient intake.

  4. Paroxysmal Perceptual Alteration: Drug-Induced Phenomenon or Schizophrenic Psychopathology?

    Science.gov (United States)

    Praharaj, Samir Kumar; Kongasseri, Sreejayan; Acharya, Mahima

    2016-01-01

    Brief and repetitive episodes of perceptual changes, termed paroxysmal perceptual alteration (PPA), have been described in association with antipsychotic treatment. We report a case of paranoid schizophrenia who had such perceptual changes akin to PPA for 15 years, which was not related to antipsychotic treatment. There was a rapid resolution of PPA after treatment with low-dose clonazepam. PMID:26954463

  5. Mitoxantrone-loaded albumin microspheres for localized intratumoral chemotherapy of breast cancer

    Science.gov (United States)

    Almond, Brett Anthony

    The safety and efficacy of conventional chemotherapy is limited by its toxicity. The direct intratumoral injection of free or microsphere-loaded antineoplastic drugs is a promising modality for the treatment of solid tumors. Intratumoral chemotherapy delivers high localized doses of cytotoxic drugs to the tumor tissues than does systemic (intravenous) chemotherapy and it decreases systemic drug concentrations and toxicities. The use of drug-loaded microspheres also provides a prolonged release of drug into the surrounding tumor tissues, increasing exposure of the neoplasm to therapeutic levels of the cytotoxic drug. Mitoxantrone and 5-fluorouracil-loaded albumin microspheres were synthesized. The microspheres were synthesized using a suspension crosslinking technique and a glutardehyde crosslinking agent. The particle-size distribution of the microspheres was controlled by adjusting the emulsion energy and the concentration of cellulose acetate butyrate, the emulsion stabilization agent. Both microsphere size and crosslink density (glutaraldehyde concentration) were found to affect the in vitro release of loaded drugs in in vitro infinite sink conditions. The in vivo efficacy and toxicity of intratumoral chemotherapy with free and microsphere-loaded mitoxantrone were evaluated in a 16/C murine mammary adenocarcinoma model. Intratumoral chemotherapy with free mitoxantrone significantly improved survival and decreased toxicity compared to intravenously delivered drug. The efficacy of two size distributions of mitoxantrone-loaded albumin microspheres, corresponding to mean diameters of 5 to 10 mum and 20 to 40 mum, were evaluated delivered both alone and in combination with free mitoxantrone. Intratumoral injection of mitoxantrone-loaded microspheres was found to allow the safe delivery of increased doses compared to free drug. The maximum tolerated doses were approximately 40 mg/kg compared to 12 mg/kg, respectively. Intratumoral chemotherapy using free and

  6. Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire

    DEFF Research Database (Denmark)

    Ostrov, David A; Grant, Barry J; Pompeu, Yuri A;

    2012-01-01

    studies have identified strong linkages between drug hypersensitivity reactions to several drugs and specific HLA alleles. One of the strongest such genetic associations found has been for the antiviral drug abacavir, which causes severe adverse reactions exclusively in patients expressing the HLA...... molecular variant B*57:01. Abacavir adverse reactions were recently shown to be driven by drug-specific activation of cytokine-producing, cytotoxic CD8(+) T cells that required HLA-B*57:01 molecules for their function; however, the mechanism by which abacavir induces this pathologic T-cell response remains...... unclear. Here we show that abacavir can bind within the F pocket of the peptide-binding groove of HLA-B*57:01, thereby altering its specificity. This provides an explanation for HLA-linked idiosyncratic adverse drug reactions, namely that drugs can alter the repertoire of self-peptides presented to T...

  7. Review: Mechanisms of How the Intestinal Microbiota Alters the Effects of Drugs and Bile Acids.

    Science.gov (United States)

    Klaassen, Curtis D; Cui, Julia Yue

    2015-10-01

    Information on the intestinal microbiota has increased exponentially this century because of technical advancements in genomics and metabolomics. Although information on the synthesis of bile acids by the liver and their transformation to secondary bile acids by the intestinal microbiota was the first example of the importance of the intestinal microbiota in biotransforming chemicals, this review will discuss numerous examples of the mechanisms by which the intestinal microbiota alters the pharmacology and toxicology of drugs and other chemicals. More specifically, the altered pharmacology and toxicology of salicylazosulfapridine, digoxin, l-dopa, acetaminophen, caffeic acid, phosphatidyl choline, carnitine, sorivudine, irinotecan, nonsteroidal anti-inflammatory drugs, heterocyclic amines, melamine, nitrazepam, and lovastatin will be reviewed. In addition, recent data that the intestinal microbiota alters drug metabolism of the host, especially Cyp3a, as well as the significance and potential mechanisms of this phenomenon are summarized. The review will conclude with an update of bile acid research, emphasizing the bile acid receptors (FXR and TGR5) that regulate not only bile acid synthesis and transport but also energy metabolism. Recent data indicate that by altering the intestinal microbiota, either by diet or drugs, one may be able to minimize the adverse effects of the Western diet by altering the composition of bile acids in the intestine that are agonists or antagonists of FXR and TGR5. Therefore, it may be possible to consider the intestinal microbiota as another drug target.

  8. Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

    DEFF Research Database (Denmark)

    Gerlinger, Marco; Rowan, Andrew J.; Horswell, Stuart;

    2012-01-01

    BACKGROUND: Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples.METHODSTo examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy...... to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.)...

  9. Intratumor temperature measurements during photodynamic therapy and hyperthermia

    International Nuclear Information System (INIS)

    Using a mammary adeno-carcinoma implanted in C/sub 3/H mice, tumor temperatures during photodynamic therapy (PDT) and hyperthermic treatments were measured. Microthermocouples made from 0.002'' copper-constantan wires were made into a linear array of 3 sensing points, 2 mm apart. These thermocouples were placed inside the tumors during each treatment. Treatments included: 1) Light (no drug) using a xenon arc lamp or an argon ion pumped dye laser, 2) PDT (with Photofrin II) using the same sources of light as above, and 3) Hyperthermia, using a heated water bath. The hyperthermic ''dose'' was 430C for 1 hour, and the light dose was 100 Joules/cm/sup 2/. Combinations of treatments were studied using light, PDT and hyperthermia. The light or PDT were followed 0 or 1 hours later with hyperthermia. Preliminary experimental data shows a difference in tumor temperature for some treatments. This difference is associated with the presence or absence of the photosensitizing drug (Photofrin II). Tumors reach higher temperatures when the drug is present and during PDT treatment. For combined treatments the intratumor temperature during the hyperthermia phase are also higher, than in identical control (hyperthermia alone) studies. Experimental data showing whether this difference is statistically significant and potential reasons for such differences will be presented

  10. Computational Analysis of Single Nucleotide Polymorphisms Associated with Altered Drug Responsiveness in Type 2 Diabetes.

    Science.gov (United States)

    Costa, Valerio; Federico, Antonio; Pollastro, Carla; Ziviello, Carmela; Cataldi, Simona; Formisano, Pietro; Ciccodicola, Alfredo

    2016-01-01

    Type 2 diabetes (T2D) is one of the most frequent mortality causes in western countries, with rapidly increasing prevalence. Anti-diabetic drugs are the first therapeutic approach, although many patients develop drug resistance. Most drug responsiveness variability can be explained by genetic causes. Inter-individual variability is principally due to single nucleotide polymorphisms, and differential drug responsiveness has been correlated to alteration in genes involved in drug metabolism (CYP2C9) or insulin signaling (IRS1, ABCC8, KCNJ11 and PPARG). However, most genome-wide association studies did not provide clues about the contribution of DNA variations to impaired drug responsiveness. Thus, characterizing T2D drug responsiveness variants is needed to guide clinicians toward tailored therapeutic approaches. Here, we extensively investigated polymorphisms associated with altered drug response in T2D, predicting their effects in silico. Combining different computational approaches, we focused on the expression pattern of genes correlated to drug resistance and inferred evolutionary conservation of polymorphic residues, computationally predicting the biochemical properties of polymorphic proteins. Using RNA-Sequencing followed by targeted validation, we identified and experimentally confirmed that two nucleotide variations in the CAPN10 gene-currently annotated as intronic-fall within two new transcripts in this locus. Additionally, we found that a Single Nucleotide Polymorphism (SNP), currently reported as intergenic, maps to the intron of a new transcript, harboring CAPN10 and GPR35 genes, which undergoes non-sense mediated decay. Finally, we analyzed variants that fall into non-coding regulatory regions of yet underestimated functional significance, predicting that some of them can potentially affect gene expression and/or post-transcriptional regulation of mRNAs affecting the splicing. PMID:27347941

  11. Computational Analysis of Single Nucleotide Polymorphisms Associated with Altered Drug Responsiveness in Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Valerio Costa

    2016-06-01

    Full Text Available Type 2 diabetes (T2D is one of the most frequent mortality causes in western countries, with rapidly increasing prevalence. Anti-diabetic drugs are the first therapeutic approach, although many patients develop drug resistance. Most drug responsiveness variability can be explained by genetic causes. Inter-individual variability is principally due to single nucleotide polymorphisms, and differential drug responsiveness has been correlated to alteration in genes involved in drug metabolism (CYP2C9 or insulin signaling (IRS1, ABCC8, KCNJ11 and PPARG. However, most genome-wide association studies did not provide clues about the contribution of DNA variations to impaired drug responsiveness. Thus, characterizing T2D drug responsiveness variants is needed to guide clinicians toward tailored therapeutic approaches. Here, we extensively investigated polymorphisms associated with altered drug response in T2D, predicting their effects in silico. Combining different computational approaches, we focused on the expression pattern of genes correlated to drug resistance and inferred evolutionary conservation of polymorphic residues, computationally predicting the biochemical properties of polymorphic proteins. Using RNA-Sequencing followed by targeted validation, we identified and experimentally confirmed that two nucleotide variations in the CAPN10 gene—currently annotated as intronic—fall within two new transcripts in this locus. Additionally, we found that a Single Nucleotide Polymorphism (SNP, currently reported as intergenic, maps to the intron of a new transcript, harboring CAPN10 and GPR35 genes, which undergoes non-sense mediated decay. Finally, we analyzed variants that fall into non-coding regulatory regions of yet underestimated functional significance, predicting that some of them can potentially affect gene expression and/or post-transcriptional regulation of mRNAs affecting the splicing.

  12. A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds.

    Science.gov (United States)

    Bruna, Alejandra; Rueda, Oscar M; Greenwood, Wendy; Batra, Ankita Sati; Callari, Maurizio; Batra, Rajbir Nath; Pogrebniak, Katherine; Sandoval, Jose; Cassidy, John W; Tufegdzic-Vidakovic, Ana; Sammut, Stephen-John; Jones, Linda; Provenzano, Elena; Baird, Richard; Eirew, Peter; Hadfield, James; Eldridge, Matthew; McLaren-Douglas, Anne; Barthorpe, Andrew; Lightfoot, Howard; O'Connor, Mark J; Gray, Joe; Cortes, Javier; Baselga, Jose; Marangoni, Elisabetta; Welm, Alana L; Aparicio, Samuel; Serra, Violeta; Garnett, Mathew J; Caldas, Carlos

    2016-09-22

    The inter- and intra-tumor heterogeneity of breast cancer needs to be adequately captured in pre-clinical models. We have created a large collection of breast cancer patient-derived tumor xenografts (PDTXs), in which the morphological and molecular characteristics of the originating tumor are preserved through passaging in the mouse. An integrated platform combining in vivo maintenance of these PDTXs along with short-term cultures of PDTX-derived tumor cells (PDTCs) was optimized. Remarkably, the intra-tumor genomic clonal architecture present in the originating breast cancers was mostly preserved upon serial passaging in xenografts and in short-term cultured PDTCs. We assessed drug responses in PDTCs on a high-throughput platform and validated several ex vivo responses in vivo. The biobank represents a powerful resource for pre-clinical breast cancer pharmacogenomic studies (http://caldaslab.cruk.cam.ac.uk/bcape), including identification of biomarkers of response or resistance.

  13. Brain tumor chemo-radiotherapy: a study of direct intratumoral perfusion with antineoplastic drugs; Chimio-radiotherapie des tumeurs cerebrales: interet de l'injection intratumorale de drogues antineoplasiques

    Energy Technology Data Exchange (ETDEWEB)

    Rousseau, J

    2007-10-15

    High grade gliomas are aggressive tumors for which current treatments remain palliative. Radiotherapy efficacy is restricted by the surrounding brain tissue tolerance. One method based on the concomitant use of chemotherapeutic drugs and external photon irradiation has been proposed to improve the treatment outcome. The systemic administration of drugs is not effective in achieving the therapeutic level of drug needed for brain tumor treatment. This is due to the blood brain barrier (BBB) that prevents molecules passing through the vascular endothelium. Recent methods have been developed to circumvent the BBB. Among them, convection-enhanced delivery (CED) relies on the continuous infusion of a fluid containing a therapeutic agent, under a pressure gradient. It permits a homogeneous and controlled drug distribution. The aims of this study were to characterise the CED method, and then to utilize it for glioma treatment in preclinical studies. Several drugs were tested: cisplatin, carbo-platin, oxaliplatin, and iodo-deoxyuridine. Two radiation modalities were evaluated: synchrotron stereotactic radiotherapy (monochromatic beam < 100 keV) and high energy irradiation (6 MV) obtained with a conventional medical linear accelerator. The results obtained reveal that the effectiveness of the combined treatment (platinated drug plus photon irradiation) is highly related to that of the chemotherapy. The data, obtained with the platinated chemotherapy, also show that high-energy X-ray irradiation (6 MV) is as effective as synchrotron X-ray irradiation. The results broaden the applicability of this chemotherapeutic approach to clinical trials. (author)

  14. Alteration of human hepatic drug transporter activity and expression by cigarette smoke condensate.

    Science.gov (United States)

    Sayyed, Katia; Vee, Marc Le; Abdel-Razzak, Ziad; Jouan, Elodie; Stieger, Bruno; Denizot, Claire; Parmentier, Yannick; Fardel, Olivier

    2016-07-01

    Smoking is well-known to impair pharmacokinetics, through inducing expression of drug metabolizing enzymes. In the present study, we demonstrated that cigarette smoke condensate (CSC) also alters activity and expression of hepatic drug transporters, which are now recognized as major actors of hepatobiliary elimination of drugs. CSC thus directly inhibited activities of sinusoidal transporters such as OATP1B1, OATP1B3, OCT1 and NTCP as well as those of canalicular transporters like P-glycoprotein, MRP2, BCRP and MATE1, in hepatic transporters-overexpressing cells. CSC similarly counteracted constitutive OATP, NTCP and OCT1 activities in human highly-differentiated hepatic HepaRG cells. In parallel, CSC induced expression of BCRP at both mRNA and protein level in HepaRG cells, whereas it concomitantly repressed mRNA expression of various transporters, including OATP1B1, OATP2B1, OAT2, NTCP, OCT1 and BSEP, and enhanced that of MRP4. Such changes in transporter gene expression were found to be highly correlated to those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin, a reference activator of the aryl hydrocarbon receptor (AhR) pathway, and were counteracted, for some of them, by siRNA-mediated AhR silencing. This suggests that CSC alters hepatic drug transporter levels via activation of the AhR cascade. Importantly, drug transporter expression regulations as well as some transporter activity inhibitions occurred for a range of CSC concentrations similar to those required for inducing drug metabolizing enzymes and may therefore be hypothesized to be relevant for smokers. Taken together, these data established human hepatic transporters as targets of cigarette smoke, which could contribute to known alteration of pharmacokinetics and some liver adverse effects caused by smoking. PMID:27450509

  15. Trochlear Nerve Schwannoma With Repeated Intratumoral Hemorrhage.

    Science.gov (United States)

    Liu, Pengfei; Bao, Yuhai; Zhang, Wenchuan

    2016-09-01

    Trochlear nerve schwannoma is extremely rare, with only 35 pathologically confirmed patients being reported in the literature. Here, the authors report a patient of trochlear nerve schwannoma in the prepontine cistern manifesting as facial pain and double vision and presenting the image characteristics of repeated intratumoral hemorrhage, which has never been reported in the literature. Total tumor along with a portion of the trochlear nerve was removed by using a retrosigmoid approach. Facial pain disappeared after operation, and the diplopia remained. Follow-up studies have shown no tumor recurrence for 2 years and the simultaneous alleviation of diplopia. Information regarding the clinical presentation, radiological features and surgical outcomes of trochlear nerve schwannoma are discussed and reviewed in the paper. PMID:27607129

  16. Drug Resistance Mutations Alter Dynamics of Inhibitor-Bound HIV-1 Protease.

    Science.gov (United States)

    Cai, Yufeng; Myint, Wazo; Paulsen, Janet L; Schiffer, Celia A; Ishima, Rieko; Kurt Yilmaz, Nese

    2014-08-12

    Under the selective pressure of therapy, HIV-1 protease mutants resistant to inhibitors evolve to confer drug resistance. Such mutations can impact both the dynamics and structures of the bound and unbound forms of the enzyme. Flap+ is a multidrug-resistant variant of HIV-1 protease with a combination of primary and secondary resistance mutations (L10I, G48V, I54V, V82A) and a strikingly altered thermodynamic profile for darunavir (DRV) binding relative to the wild-type protease. We elucidated the impact of these mutations on protein dynamics in the DRV-bound state using molecular dynamics simulations and NMR relaxation experiments. Both methods concur in that the conformational ensemble and dynamics of protease are impacted by the drug resistance mutations in Flap+ variant. Surprisingly this change in ensemble dynamics is different from that observed in the unliganded form of the same variant (Cai, Y. et al. J. Chem. Theory Comput. 2012, 8, 3452-3462). Our comparative analysis of both inhibitor-free and bound states presents a comprehensive picture of the altered dynamics in drug-resistant mutant HIV-1 protease and underlies the importance of incorporating dynamic analysis of the whole system, including the unliganded state, into revealing drug resistance mechanisms. PMID:25136270

  17. An intradural skull base chordoma presenting with acute intratumoral hemorrhage

    Directory of Open Access Journals (Sweden)

    Uda Takehiro

    2006-01-01

    Full Text Available We present a rare case of skull base chordoma of extraosseous intradural type that presented as acute intratumoral hemorrhage. Surgical removal of the tumor was accomplished using a skull base approach.

  18. Dramatyping: a generic algorithm for detecting reasonable temporal correlations between drug administration and lab value alterations.

    Science.gov (United States)

    Newe, Axel

    2016-01-01

    According to the World Health Organization, one of the criteria for the standardized assessment of case causality in adverse drug reactions is the temporal relationship between the intake of a drug and the occurrence of a reaction or a laboratory test abnormality. This article presents and describes an algorithm for the detection of a reasonable temporal correlation between the administration of a drug and the alteration of a laboratory value course. The algorithm is designed to process normalized lab values and is therefore universally applicable. It has a sensitivity of 0.932 for the detection of lab value courses that show changes in temporal correlation with the administration of a drug and it has a specificity of 0.967 for the detection of lab value courses that show no changes. Therefore, the algorithm is appropriate to screen the data of electronic health records and to support human experts in revealing adverse drug reactions. A reference implementation in Python programming language is available.

  19. Dramatyping: a generic algorithm for detecting reasonable temporal correlations between drug administration and lab value alterations.

    Science.gov (United States)

    Newe, Axel

    2016-01-01

    According to the World Health Organization, one of the criteria for the standardized assessment of case causality in adverse drug reactions is the temporal relationship between the intake of a drug and the occurrence of a reaction or a laboratory test abnormality. This article presents and describes an algorithm for the detection of a reasonable temporal correlation between the administration of a drug and the alteration of a laboratory value course. The algorithm is designed to process normalized lab values and is therefore universally applicable. It has a sensitivity of 0.932 for the detection of lab value courses that show changes in temporal correlation with the administration of a drug and it has a specificity of 0.967 for the detection of lab value courses that show no changes. Therefore, the algorithm is appropriate to screen the data of electronic health records and to support human experts in revealing adverse drug reactions. A reference implementation in Python programming language is available. PMID:27042396

  20. Collections of simultaneously altered genes as biomarkers of cancer cell drug response.

    Science.gov (United States)

    Masica, David L; Karchin, Rachel

    2013-03-15

    Computational analysis of cancer pharmacogenomics data has resulted in biomarkers predictive of drug response, but the majority of response is not captured by current methods. Methods typically select single biomarkers or groups of related biomarkers but do not account for response that is strictly dependent on many simultaneous genetic alterations. This shortcoming reflects the combinatorics and multiple-testing problem associated with many-body biologic interactions. We developed a novel approach, Multivariate Organization of Combinatorial Alterations (MOCA), to partially address these challenges. Extending on previous work that accounts for pairwise interactions, the approach rapidly combines many genomic alterations into biomarkers of drug response, using Boolean set operations coupled with optimization; in this framework, the union, intersection, and difference Boolean set operations are proxies of molecular redundancy, synergy, and resistance, respectively. The algorithm is fast, broadly applicable to cancer genomics data, is of immediate use for prioritizing cancer pharmacogenomics experiments, and recovers known clinical findings without bias. Furthermore, the results presented here connect many important, previously isolated observations.

  1. Intratumoral Hemorrhage in a Patient With Cerebellar Hemangioblastoma

    Science.gov (United States)

    Wang, Zhen; Hu, Jun; Xu, Liang; Malaguit, Jay; Chen, Sheng

    2015-01-01

    Abstract Spontaneous hemorrhage is rarely associated with hemangioblastomas. Intratumoral hemorrhage occurring in cerebellar hemangioblastomas is more rare. A 25-year-old man was admitted to our hospital with headache. We found a round cystic lesion with solid part in the right cerebellum. The lesion was resected. The final pathological diagnosis was hemangioblastomas. The radiological features of this case were similar to normal hemangioblastomas, whereas our histological examination showed the occurrence of the intratumoral hemorrhage. If the hemangioblastoma ruptures in our case, the outcome of the patient will be worse. It is difficult to identify the intratumoral hemorrhage of hemangioblastomas and quite dangerous if it is diagnosed late. Diagnosing an intratumoral hemorrhage of hemangioblastomas still needs a further discussion. Genetic screening may help us make an early diagnosis. Furthermore, the mechanism about intratumoral hemorrhage of hemangioblastomas remains unknown. The mutation of D6Mit135 gene on chromosome 6 may be responsible for the vascular dilation and hemorrhage induction in the hemangioblastomas. Tumor size, upregulation of vascular endothelial growth factor, spinalradicular location, and solid type are also factors relating to the hemorrhage of hemangioblastomas. The purpose of reporting our case is 2-fold: to remind clinicians to consider the possibility of internal hemorrhaging while diagnosing this disease, and provide a starting point to discuss mechanisms regarding the intratumoral hemorrhage of hemangioblastomas. PMID:25634201

  2. Direct intratumoral infusion of liposome encapsulated rhenium radionuclides for cancer therapy: Effects of nonuniform intratumoral dose distribution

    International Nuclear Information System (INIS)

    Purpose: Focused radiation therapy by direct intratumoral infusion of lipid nanoparticle (liposome)-carried beta-emitting radionuclides has shown promising results in animal model studies; however, little is known about the impact the intratumoral liposomal radionuclide distribution may have on tumor control. The primary objective of this work was to investigate the effects the intratumoral absorbed dose distributions from this cancer therapy modality have on tumor control and treatment planning by combining dosimetric and radiobiological modeling with in vivo imaging data. Methods: 99mTc-encapsulated liposomes were intratumorally infused with a single injection location to human head and neck squamous cell carcinoma xenografts in nude rats. High resolution in vivo planar imaging was performed at various time points for quantifying intratumoral retention following infusion. The intratumoral liposomal radioactivity distribution was obtained from 1 mm resolution pinhole collimator SPECT imaging coregistered with CT imaging of excised tumors at 20 h postinfusion. Coregistered images were used for intratumoral dosimetric and radiobiological modeling at a voxel level following extrapolation to the therapeutic analogs, 186Re/188Re liposomes. Effective uniform dose (EUD) and tumor control probability (TCP) were used to assess therapy effectiveness and possible methods of improving upon tumor control with this radiation therapy modality. Results: Dosimetric analysis showed that average tumor absorbed doses of 8.6 Gy/MBq (318.2 Gy/mCi) and 5.7 Gy/MBq (209.1 Gy/mCi) could be delivered with this protocol of radiation delivery for 186Re/188Re liposomes, respectively, and 37-92 MBq (1-2.5 mCi)/g tumor administered activity; however, large intratumoral absorbed dose heterogeneity, as seen in dose-volume histograms, resulted in insignificant values of EUD and TCP for achieving tumor control. It is indicated that the use of liposomes encapsulating radionuclides with higher energy

  3. Sex-related differences in cadmium-induced alteration of drug action in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Schnell, R.C.; Pence, D.H.; Prosser, T.D.; Miya, T.S.

    1976-01-01

    Three days after pretreatment of rats of both sexes with cadmium (2 mg/kg, i.p.), the duration of hypnosis induced by hexobarbital (75 mg/kg, i.p.) was potentiated in males but not females. Likewise, similar treatment with cadmium leads to significant inhibition of the metabolism of hexobarbital by hepatic microsomal enzymes obtained from male but not female animals. These data suggest that there is a sex-related difference in the ability of cadmium to alter drug action in rats.

  4. Biological activity and safety of adenoviral vector-expressed wild-type p53 after intratumoral injection in melanoma and breast cancer patients with p53-overexpressing tumors

    NARCIS (Netherlands)

    Dummer, R; Bergh, J; Karlsson, Y; Horovitz, JA; Mulder, NH; Huinin, DT; Burg, G; Hofbauer, G; Osanto, S

    2000-01-01

    p53 mutations are common genetic alterations in human cancer. Gene transfer of a wild-type (wt) p53 gene reverses the loss of normal p53 function in vitro and in vivo. A phase I dose escalation study of single intratumoral (i.t.) injection of a replication-defective adenoviral expression vector cont

  5. Succinobucol’s New Coat — Conjugation with Steroids to Alter Its Drug Effect and Bioavailability

    Directory of Open Access Journals (Sweden)

    Satu Ikonen

    2011-11-01

    Full Text Available Synthesis, detailed structural characterization (X-ray, NMR, MS, IR, elemental analysis, and studies of toxicity, antioxidant activity and bioavailability of unique potent anti-atherosclerotic succinobucol-steroid conjugates are reported. The conjugates consist of, on one side, the therapeutically important drug succinobucol ([4-{2,6-di-tert-butyl-4-[(1-{[3-tert-butyl-4-hydroxy-5-(propan-2-ylphenyl]sulfanyl}ethylsulfanyl]phenoxy}-4-oxo-butanoic acid] possessing an antioxidant and anti-inflammatory activity, and on the other side, plant stanol/sterols (stigmastanol, β-sitosterol and stigmasterol possessing an ability to lower the blood cholesterol level. A cholesterol-succinobucol prodrug was also prepared in order to enhance the absorption of succinobucol through the intestinal membrane into the organism and to target the drug into the place of lipid metabolism—The enterohepatic circulation system. Their low toxicity towards mice fibroblasts at maximal concentrations, their antioxidant activity, comparable or even higher than that of ascorbic acid as determined by direct quenching of the DPPH radical, and their potential for significantly altering total and LDL cholesterol levels, suggest that these conjugates merit further studies in the treatment of cardiovascular or other related diseases. A brief discussion of succinobucol’s ability to quench the radicals, supported with a computational model of the electrostatic potential mapped on the electron density surface of the drug, is also presented.

  6. Prenatal drug exposure to illicit drugs alters working memory-related brain activity and underlying network properties in adolescence.

    Science.gov (United States)

    Schweitzer, Julie B; Riggins, Tracy; Liang, Xia; Gallen, Courtney; Kurup, Pradeep K; Ross, Thomas J; Black, Maureen M; Nair, Prasanna; Salmeron, Betty Jo

    2015-01-01

    The persistence of effects of prenatal drug exposure (PDE) on brain functioning during adolescence is poorly understood. We explored neural activation to a visuospatial working memory (VSWM) versus a control task using functional magnetic resonance imaging (fMRI) in adolescents with PDE and a community comparison group (CC) of non-exposed adolescents. We applied graph theory metrics to resting state data using a network of nodes derived from the VSWM task activation map to further explore connectivity underlying WM functioning. Participants (ages 12-15 years) included 47 adolescents (27 PDE and 20 CC). All analyses controlled for potentially confounding differences in birth characteristics and postnatal environment. Significant group by task differences in brain activation emerged in the left middle frontal gyrus (BA 6) with the CC group, but not the PDE group, activating this region during VSWM. The PDE group deactivated the culmen, whereas the CC group activated it during the VSWM task. The CC group demonstrated a significant relation between reaction time and culmen activation, not present in the PDE group. The network analysis underlying VSWM performance showed that PDE group had lower global efficiency than the CC group and a trend level reduction in local efficiency. The network node corresponding to the BA 6 group by task interaction showed reduced nodal efficiency and fewer direct connections to other nodes in the network. These results suggest that adolescence reveals altered neural functioning related to response planning that may reflect less efficient network functioning in youth with PDE.

  7. Intratumor photosensitizer injection for photodynamic therapy: Pre-clinical experience with methylene blue, Pc 4, and Photofrin

    Science.gov (United States)

    Baran, Timothy M.; Foster, Thomas H.

    2016-03-01

    Intravenous administration of some photosensitizers, including the FDA-approved Photofrin, results in significant systemic photosensitivity and a 2-3-day drug-light interval. Direct intratumor injection of photosensitizer could potentially eliminate these negative aspects of photodynamic therapy (PDT), while requiring a lower photosensitizer dose to achieve comparable drug concentration in the target tissue. We performed PDT using intratumor injection of 3 photosensitizers, methylene blue (MB), Pc 4, and Photofrin, in mouse tumor models. After a 0-15 minute drug-light interval, illumination was delivered by appropriate diode lasers. For animals receiving MB or Pc 4, surface illumination was delivered using a microlens-terminated fiber. For animals receiving Photofrin, interstitial illumination was delivered by a 1 cm diffuser. In animals receiving MB or Pc 4, tumor dimensions were measured daily post-PDT, with a cure being defined as no palpable tumor 90 days post-treatment. For Photofrin, animals were sacrificed 24 hours post-PDT and tumors were excised, with samples HE stained to assess PDT-induced necrosis. 55% of tumors were cured with MB-PDT, and significant tumor growth delay (p=0.002) was observed for Pc 4. For Photofrin PDT, the mean necrosis radius was 3.4+/-0.8 mm, compared to 2.9+/-1.3 mm for systemic administration, which was not a significant difference (p=0.58). Intratumoral injection of the photosensitizers methylene blue, Pc 4, and Photofrin is feasible, and results in appreciable tumor response. Further investigation is necessary to optimize treatment protocols and assess the systemic photosensitivity induced by intratumor injection.

  8. Temperature-Sensitive Gels for Intratumoral Delivery of β-Lapachone: Effect of Cyclodextrins and Ethanol

    Directory of Open Access Journals (Sweden)

    Marcilio S. S. Cunha-Filho

    2012-01-01

    Full Text Available This work evaluated the potential of Pluronics (varieties F127 and P123 in combination with solubilizing agents to be used as syringeable in situ gelling depots of intratumoral β-lapachone (βLAP. Pluronic dispersions prepared at various concentrations in the absence and the presence of ethanol and randomly methylated β-cyclodextrin (RMβCD were characterized regarding their rheological properties, drug solubilization capacity, and in vitro release. Pluronic F127 (18–23% formulations combined high ability to solubilize βLAP (enhancement solubility factor up to 50, adequate gel temperature range (over 25°C, and gel strength at 37°C enough to guarantee the permanence of the formulation in the administration site for a period of time. βLAP release rate was finely tuned by the concentration of the polymer and the addition of RMβCD (diffusion coefficient ranging between 9 and 69 μg·cm−2. The ethanol increases βLAP release rate but simultaneously led to weak gels. This paper shows that βLAP formulations involving temperature-reversible Pluronic gels may be suitable for intratumoral drug delivery purposes.

  9. Intratumoral radioimmunotherapy of a human colon cancer xenograft using a sustained-release gel

    International Nuclear Information System (INIS)

    Low tumor uptake and normal tissue toxicity limit the efficacy of RIT for the treatment of solid tumors. In this study, an intratumoral injectable gel drug delivery system for local administration of RIT was evaluated using the LS174T human colon cancer xenograft model in SCID mice. The injectable gel is a collagen-based drug delivery system designed for intratumoral (i.t.) administration, which has previously been shown to enhance drug retention at the injection site and reduce systemic drug exposure. We compared the local (tumor) retention and biodistribution of 111In-labeled NR-LU-10 monoclonal antibody given i.t. in the injectable gel versus simple aqueous solution. 111In gel given i.t. and 111In-NR-LU-10 given intraperitoneally (i.p.) were used as controls. The results showed that tumors treated with 111In-NR-LU-10 gel maintained the highest levels of radioactivity for up to 96 h. At 48 h after the administration of 111In-NR-LU-10 gel i.t., 111In-NR-LU-10 solution i.t., 111In gel i.t., or111 In-NR-LU-10 i.p., the level of radioactivity remaining in each gram of tumor was 98, 49, 45, and 16% of the injected dose, respectively. It was estimated that if 100 μCi of 90Y-NR-LU-10 were administered similarly, tumor treated with 90Y-NR-LU-10 gel i.t. would receive a dose of 90.0 Gy, whereas normal tissues in the same animal would receive a dose of approximately 2.43 Gy. In contrast, if 90Y-NR-LU-10 were delivered i.p., a comparable tumor would receive a dose of 16.8 Gy and corresponding normal tissues would receive 3.36 Gy. Consistent with these estimates, enhanced antitumor efficacy was observed when 90Y-NR-LU-10 gel was administered i.t. Tumor growth delay time was 6.9-fold (P 90Y-NR-LU-10 i.p. (2.1 days). Systemic toxicity was also significantly reduced in gel-treated animals as monitored by loss of body weight. This study demonstrated that intratumoral delivery of 90Y-NR-LU-10 gel markedly increased the retention of the radioisotope in tumors, enhanced the

  10. Intratumor heterogeneity, variability and plasticity: questioning the current concepts in classification and treatment of hepatocellular carcinoma.

    Science.gov (United States)

    Weiskirchen, Ralf

    2016-04-01

    In the classical view, the formation of a primary tumor is the consequence of a mutational event that first affects a single cell that subsequently passes through a multitude of consecutive hyperplastic and dysplastic stages. At the end of this pathogenetic sequence a cell arises that is potentially able to expanse infinitely having capacity to form a homogenous tumor mass. In contrary to this clonal expansion concept, the majority of primary human tumors display already a startling heterogeneity that can be reflected in different morphological features, physiological activities, and genetic diversity. In the past it was speculated that this cancer cell plasticity within a tumor is the result of an adaptive process that is induced by specific inhibiting therapies. In regard to the formation of hepatocellular carcinoma (HCC) this dogma was once challenged in a recent study that analysed tumor areas that were taken from HCC patients without medical pretreatment. Most of the analyzed samples showed highly significant intratumor heterogeneity. This affected morphological attributes, immunohistochemical stainability of five tumor-associated markers [α-fetoprotein (AFP), EpCAM, CK7, CD44 and glutamine synthetase], and integrity of genes (β-catenin and p53) that are critically involved in the pathogenesis of HCC. Altogether, this study showed that intratumor heterogeneity is a frequent finding in HCC that may contribute to treatment failure and drug resistance in HCC patients. PMID:27115013

  11. A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds.

    Science.gov (United States)

    Bruna, Alejandra; Rueda, Oscar M; Greenwood, Wendy; Batra, Ankita Sati; Callari, Maurizio; Batra, Rajbir Nath; Pogrebniak, Katherine; Sandoval, Jose; Cassidy, John W; Tufegdzic-Vidakovic, Ana; Sammut, Stephen-John; Jones, Linda; Provenzano, Elena; Baird, Richard; Eirew, Peter; Hadfield, James; Eldridge, Matthew; McLaren-Douglas, Anne; Barthorpe, Andrew; Lightfoot, Howard; O'Connor, Mark J; Gray, Joe; Cortes, Javier; Baselga, Jose; Marangoni, Elisabetta; Welm, Alana L; Aparicio, Samuel; Serra, Violeta; Garnett, Mathew J; Caldas, Carlos

    2016-09-22

    The inter- and intra-tumor heterogeneity of breast cancer needs to be adequately captured in pre-clinical models. We have created a large collection of breast cancer patient-derived tumor xenografts (PDTXs), in which the morphological and molecular characteristics of the originating tumor are preserved through passaging in the mouse. An integrated platform combining in vivo maintenance of these PDTXs along with short-term cultures of PDTX-derived tumor cells (PDTCs) was optimized. Remarkably, the intra-tumor genomic clonal architecture present in the originating breast cancers was mostly preserved upon serial passaging in xenografts and in short-term cultured PDTCs. We assessed drug responses in PDTCs on a high-throughput platform and validated several ex vivo responses in vivo. The biobank represents a powerful resource for pre-clinical breast cancer pharmacogenomic studies (http://caldaslab.cruk.cam.ac.uk/bcape), including identification of biomarkers of response or resistance. PMID:27641504

  12. Inter- and intratumoral heterogeneity of BCL2 correlates with IgH expression and prognosis in follicular lymphoma

    International Nuclear Information System (INIS)

    Most follicular lymphomas (FLs) are genetically defined by the t(14;18)(q32;q21) translocation that juxtaposes the BCL2 gene to the immunoglobulin heavy chain (IgH) 3' regulatory regions (IgH-3'RRs). Despite this recurrent translocation, FL cases are heterogeneous in terms of intratumoral clonal diversity for acquired mutations and variations in the tumor microenvironment. Here we describe an additional mechanism that contributes to inter- and intratumoral heterogeneity in FLs. By applying a novel single-molecule RNA fluorescence-based in situ hybridization (FISH) technique to detect mRNA molecules of BCL2 and IgH in single cells, we found marked heterogeneity in the number of BCL2 mRNA transcripts within individual lymphoma cells. Moreover, BCL2 mRNA molecules correlated with IgH mRNA molecules in individual cells both in t(14;18) lymphoma cell lines and in patient samples. Consistently, a strong correlation between BCL2 and IgH protein levels was found in a series of 205 primary FL cases by flow cytometry and immunohistochemistry. Inter- and intratumoral heterogeneity of BCL2 expression determined resistance to drugs commonly used in FL treatment and affected overall survival of FL patients. These data demonstrate that BCL2 and IgH expressions are heterogeneous and coregulated in t(14;18)-translocated cells, and determine the response to therapy in FL patients

  13. Alterations in Polysomnographic (PSG profile in drug-naïve Parkinson′s disease

    Directory of Open Access Journals (Sweden)

    Sanju P Joy

    2014-01-01

    Full Text Available Objective: We studied the changes in Polysomnographic (PSG profile in drug-naïve patients of Parkinson′s disease (PD who underwent evaluation with sleep overnight PSG. Materials and Methods: This prospective study included 30 with newly diagnosed levodopa-naïve patients with PD, fulfilling the UK-PD society brain bank clinical diagnostic criteria (M:F = 25:5; age: 57.2 ± 10.7 years. The disease severity scales and sleep related questionnaires were administered, and then patients were subjected to overnight PSG. Results: The mean duration of illness was 9.7 ± 9.5 months. The mean Hoehn and Yahr stage was 1.8 ± 0.4. The mean Unified Parkinson′s Disease Rating Scale (UPDRS motor score improved from 27.7 ± 9.2 to 17.5 ± 8.9 with sustained usage of levodopa. Nocturnal sleep as assessed by Pittsburgh Sleep Quality Index (PSQI was impaired in 10 (33.3% patients (mean PSQI score: 5.1 ± 3.1. Excessive day time somnolence was recorded in three patients with Epworth Sleepiness Scale (ESS score ≥ 10 (mean ESS score: 4.0 ± 3.4. PSG analysis revealed that poor sleep efficiency of <85% was present in 86.7% of patients (mean: 68.3 ± 21.3%. The latencies to sleep onset (mean: 49.8 ± 67.0 minutes and stage 2 sleep (36.5 ± 13.1% were prolonged while slow wave sleep was shortened. Respiration during sleep was significantly impaired in which 43.3% had impaired apnoea hyperpnoea index (AHI ≥5, mean AHI: 8.3 ± 12.1. Apnoeic episodes were predominantly obstructive (obstructive sleep apnea, OSA index = 2.2 ± 5.1. These patients had periodic leg movement (PLM disorder (56.7% had PLM index of 5 or more, mean PLMI: 27.53 ± 4 9.05 that resulted in excessive daytime somnolence. Conclusions: To conclude, sleep macro-architecture is altered in frequently and variably in levodopa-naοve patients of PD and the alterations are possibly due to disease process per se.

  14. Intratumoral Hemorrhage in a Patient With Cerebellar Hemangioblastoma

    OpenAIRE

    Wang, Zhen; Hu, Jun; Xu, Liang; Malaguit, Jay; Chen, Sheng

    2015-01-01

    Abstract Spontaneous hemorrhage is rarely associated with hemangioblastomas. Intratumoral hemorrhage occurring in cerebellar hemangioblastomas is more rare. A 25-year-old man was admitted to our hospital with headache. We found a round cystic lesion with solid part in the right cerebellum. The lesion was resected. The final pathological diagnosis was hemangioblastomas. The radiological features of this case were similar to normal hemangioblastomas, whereas our histological examination showed ...

  15. Surgical treatment of hepatocellular carcinoma with severe intratumoral arterioportal shunt

    Institute of Scientific and Technical Information of China (English)

    Hiromichi; Ishii; Teruhisa; Sonoyama; Shingo; Nakashima; Hiroyuki; Nagata; Atsushi; Shiozaki; Yoshiaki; Kuriu; Hisashi; Ikoma; Masayoshi; Nakanishi; Daisuke; Ichikawa; Hitoshi; Fujiwara; Kazuma; Okamoto; Toshiya; Ochiai; Yukihito; Kokuba; Chohei; Sakakura; Eigo; Otsuji

    2010-01-01

    We report a case of hepatocellular carcinoma (HCC) that caused a severe arterioportal shunt (APS). A 49-year-old man was admitted to hospital due to esophagogastric variceal hemorrhage and HCC, and underwent endoscopic variceal ligation (EVL) and endoscopic injection sclerotherapy (EIS). He was then referred to our hospital. Abdominal computed tomography revealed a lowdensity lesion in the posterior segment of the liver and an intratumoral APS, which caused portal hypertension. Although the patient underwen...

  16. Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire

    OpenAIRE

    Ostrov, David A.; Grant, Barry J.; Pompeu, Yuri A.; Sidney, John; Harndahl, Mikkel; Southwood, Scott; Oseroff, Carla; Lu, Shun; Jakoncic, Jean; de Oliveira, Cesar Augusto F; Yang, Lun; Mei, Hu; Shi, Leming; Shabanowitz, Jeffrey; English, A. Michelle

    2012-01-01

    Idiosyncratic adverse drug reactions are unpredictable, dose independent and potentially life threatening; this makes them a major factor contributing to the cost and uncertainty of drug development. Clinical data suggest that many such reactions involve immune mechanisms, and genetic association studies have identified strong linkage between drug hypersensitivity reactions to several drugs and specific HLA alleles. One of the strongest such genetic associations found has been for the antivir...

  17. CRISPR-Barcoding for Intratumor Genetic Heterogeneity Modeling and Functional Analysis of Oncogenic Driver Mutations.

    Science.gov (United States)

    Guernet, Alexis; Mungamuri, Sathish Kumar; Cartier, Dorthe; Sachidanandam, Ravi; Jayaprakash, Anitha; Adriouch, Sahil; Vezain, Myriam; Charbonnier, Françoise; Rohkin, Guy; Coutant, Sophie; Yao, Shen; Ainani, Hassan; Alexandre, David; Tournier, Isabelle; Boyer, Olivier; Aaronson, Stuart A; Anouar, Youssef; Grumolato, Luca

    2016-08-01

    Intratumor genetic heterogeneity underlies the ability of tumors to evolve and adapt to different environmental conditions. Using CRISPR/Cas9 technology and specific DNA barcodes, we devised a strategy to recapitulate and trace the emergence of subpopulations of cancer cells containing a mutation of interest. We used this approach to model different mechanisms of lung cancer cell resistance to EGFR inhibitors and to assess effects of combined drug therapies. By overcoming intrinsic limitations of current approaches, CRISPR-barcoding also enables investigation of most types of genetic modifications, including repair of oncogenic driver mutations. Finally, we used highly complex barcodes inserted at a specific genome location as a means of simultaneously tracing the fates of many thousands of genetically labeled cancer cells. CRISPR-barcoding is a straightforward and highly flexible method that should greatly facilitate the functional investigation of specific mutations, in a context that closely mimics the complexity of cancer. PMID:27453044

  18. Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer

    Science.gov (United States)

    Koay, Eugene J.; Baio, Flavio E.; Ondari, Alexander; Truty, Mark J.; Cristini, Vittorio; Thomas, Ryan M.; Chen, Rong; Chatterjee, Deyali; Kang, Ya'an; Zhang, Joy; Court, Laurence; Bhosale, Priya R.; Tamm, Eric P.; Qayyum, Aliya; Crane, Christopher H.; Javle, Milind; Katz, Matthew H.; Gottumukkala, Vijaya N.; Rozner, Marc A.; Shen, Haifa; Lee, Jeffrey E.; Wang, Huamin; Chen, Yuling; Plunkett, William; Abbruzzese, James L.; Wolff, Robert A.; Maitra, Anirban; Ferrari, Mauro; Varadhachary, Gauri R.; Fleming, Jason B.

    2014-12-01

    There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of

  19. Effects of sorafenib on intra-tumoral interstitial fluid pressure and circulating biomarkers in patients with refractory sarcomas (NCI protocol 6948.

    Directory of Open Access Journals (Sweden)

    Chandrajit P Raut

    Full Text Available PURPOSE: Sorafenib is a multi-targeted tyrosine kinase inhibitor with therapeutic efficacy in several malignancies. Sorafenib may exert its anti-neoplastic effect in part by altering vascular permeability and reducing intra-tumoral interstitial hypertension. As correlative science with a phase II study in patients with advanced soft-tissue sarcomas (STS, we evaluated the impact of this agent on intra-tumor interstitial fluid pressure (IFP, serum circulating biomarkers, and vascular density. PATIENTS AND METHODS: Patients with advanced STS with measurable disease and at least one superficial lesion amenable to biopsy received sorafenib 400 mg twice daily. Intratumoral IFP and plasma and circulating cell biomarkers were measured before and after 1-2 months of sorafenib administration. Results were analyzed in the context of the primary clinical endpoint of time-to-progression (TTP. RESULTS: In 15 patients accrued, the median TTP was 45 days (range 14-228. Intra-tumoral IFP measurements obtained in 6 patients at baseline showed a direct correlation with tumor size. Two patients with stable disease at two months had post-sorafenib IFP evaluations and demonstrated a decline in IFP and vascular density. Sorafenib significantly increased plasma VEGF, PlGF, and SDF1α and decreased sVEGFR-2 levels. Increased plasma SDF1α and decreased sVEGFR-2 levels on day 28 correlated with disease progression. CONCLUSIONS: Pretreatment intra-tumoral IFP correlated with tumor size and decreased in two evaluable patients with SD on sorafenib. Sorafenib also induced changes in circulating biomarkers consistent with expected VEGF pathway blockade, despite the lack of more striking clinical activity in this small series. TRIAL REGISTRATION: ClinicalTrials.gov NCT00330421.

  20. The Utility of Impulsive Bias and Altered Decision Making as Predictors of Drug Efficacy and Target Selection: Rethinking Behavioral Screening for Antidepressant Drugs.

    Science.gov (United States)

    Marek, Gerard J; Day, Mark; Hudzik, Thomas J

    2016-03-01

    Cognitive dysfunction may be a core feature of major depressive disorder, including affective processing bias, abnormal response to negative feedback, changes in decision making, and increased impulsivity. Accordingly, a translational medicine paradigm predicts clinical action of novel antidepressants by examining drug-induced changes in affective processing bias. With some exceptions, these concepts have not been systematically applied to preclinical models to test new chemical entities. The purpose of this review is to examine whether an empirically derived behavioral screen for antidepressant drugs may screen for compounds, at least in part, by modulating an impulsive biasing of responding and altered decision making. The differential-reinforcement-of-low-rate (DRL) 72-second schedule is an operant schedule with a documented fidelity for discriminating antidepressant drugs from nonantidepressant drugs. However, a theoretical basis for this empirical relationship has been lacking. Therefore, this review will discuss whether response bias toward impulsive behavior may be a critical screening characteristic of DRL behavior requiring long inter-response times to obtain rewards. This review will compare and contrast DRL behavior with the five-choice serial reaction time task, a test specifically designed for assessing motoric impulsivity, with respect to psychopharmacological testing and the neural basis of distributed macrocircuits underlying these tasks. This comparison suggests that the existing empirical basis for the DRL 72-second schedule as a pharmacological screen for antidepressant drugs is complemented by a novel hypothesis that altering impulsive response bias for rodents trained on this operant schedule is a previously unrecognized theoretical cornerstone for this screening paradigm. PMID:26699144

  1. Intratumoral chemotherapy for lung cancer: re-challenge current targeted therapies

    Directory of Open Access Journals (Sweden)

    Hohenforst-Schmidt W

    2013-07-01

    through passive transport within the tumor. Recent advances have enhanced the diffusion of pharmaceuticals through active transport by using pharmaceuticals designed to target the genome of tumors. In the present study, five patients with non-small cell lung cancer epidermal growth factor receptor (EGFR negative stage IIIa–IV International Union Against Cancer 7 (UICC-7, and with Eastern Cooperative Oncology Group (ECOG 2 scores were administered platinum-based doublet chemotherapy using combined intratumoral-regional and intravenous route of administration. Cisplatin analogues were injected at 0.5%–1% concentration within the tumor lesion and proven malignant lymph nodes according to pretreatment histological/cytological results and the concentration of systemic infusion was decreased to 70% of a standard protocol. This combined intravenous plus intratumoral-regional chemotherapy is used as a first line therapy on this short series of patients. To the best of our knowledge this is the first report of direct treatment of involved lymph nodes with cisplatin by endobronchial ultrasound drug delivery with a needle without any adverse effects. The initial overall survival and local response are suggestive of a better efficacy compared to established doublet cisplatin–based systemic chemotherapy in (higher standard concentrations alone according to the UICC 7 database expected survival. An extensive search of the literature was performed to gather information of previously published literature of intratumoral chemo-drug administration and formulation for this treatment modality. Our study shows a favorable local response, more than a 50% reduction, for a massive tumor mass after administration of five sessions of intratumoral chemotherapy plus two cycles of low-dose intravenous chemotherapy according to our protocol. These encouraging results (even in very sick ECOG 2 patients with central obstructive non-small cell lung cancer having a worse prognosis and quality of

  2. Boceprevir in combination with HIV protease inhibitors in patients with advanced fibrosis-altered drug-drug interactions?

    Directory of Open Access Journals (Sweden)

    C Schwarze-Zander

    2012-11-01

    Full Text Available In HIV/HCV co-infected patients improved treatment outcomes have been reported for the HCV protease inhibitors (PIs boceprevir (BOC and telaprevir (TVR, reaching SVR rates of up to 70% in pilot trials. Due to complex drug-drug-interactions triple therapy is substantially limited in HIV/HCV-coinfected individuals. Co-administration of BOC with the commonly available HIV PIs has been reported not only to decrease the level of BOC but also to lead to relevant decreases in the respective HIV PI. Here, we report on two patients who received BOC-containing HCV triple therapy in combination with a HIV PI. Patient 1 was on darunavir 800 mg/ritonavir 100 mg once-daily mono-therapy. Using FibroScan a liver stiffness of 34 kPa suggested liver cirrhosis prior to start of HCV triple therapy. At week 5 of HCV triple therapy darunavir trough concentration was measured in the reference range with 3777 ng/ml (reference trough concentration 2400–4600 ng/ml. HCV-RNA became negative at week 10 and HIV-RNA was below detection limit (<40 copies/ml at all times. Patient 2 was on a simplified FTC qd and fos-amprenavir 700 mg/ritonavir 100 mg bid regimen. Liver disease had also progressed to liver cirrhosis, confirmed in FibroScan, with a liver stiffness of 32 kPa. At week 8 of HCV triple therapy fos-amprenavir trough level was measured in the normal reference range with 1699 ng/ml (reference trough concentration 750–2500 ng/ml. At week 11 HCV-RNA was <12 IU/ml and HIV viral load was below detection limit of <40 copies/ml at all times. Our clinical data suggest that in patients with advanced liver disease possibly drug levels of HIV PIs which are coadministered with BOC may be within the normal range. In order to better understand the true amount of drug interactions between BOC and commonly used HIV PIs in HIV/HCV-coinfected patients with more advanced liver fibrosis, urgently more PK studies are required to make HCV triple therapy accessible for a wider number of

  3. Intratumoral heterogeneity of microRNA expression in breast cancer.

    Science.gov (United States)

    Raychaudhuri, Mithu; Schuster, Tibor; Buchner, Theresa; Malinowsky, Katharina; Bronger, Holger; Schwarz-Boeger, Ulrike; Höfler, Heinz; Avril, Stefanie

    2012-07-01

    Profiling studies have identified specific microRNA (miRNA) signatures in malignant tumors including breast cancer. Our aim was to assess intratumoral heterogeneity in miRNA expression levels within primary breast cancers and between axillary lymph node metastases from the same patient. Specimens of 16 primary breast cancers were sampled in 8-10 distinct locations including the peripheral, intermediate, and central tumor zones, as well as two to five axillary lymph node metastases (n = 9). Total RNA was extracted from 132 paraffin-embedded samples, and the expression of miR-10b, miR-210, miR-31, and miR-335 was assessed as well as the reproducibility of RNA extraction and miRNA analysis by quantitative RT-PCR. Considerable intratumoral heterogeneity existed for all four miRNAs within primary breast cancers (CV 40%). No significant differences within (CV 34%) or between different tumor zones (CV 33%) were found. A similar variation in miRNA expression was observed between corresponding lymph node metastases (mean CV 40%). In comparison, the variation among different patients showed a CV of 80% for primary tumors and 103% for lymph node metastases. Both miRNA extraction procedures and quantitative RT-PCR showed high reproducibility (CV ≤ 2%). Thus, the intratumoral heterogeneity of miRNA expression in breast cancers can lead to significant sampling bias. Assessment of breast cancer miRNA profiles may require sampling at several different tumor locations and of several tumor-involved lymph nodes when deriving miRNA expression profiles of metastases.

  4. Intratumoral Heterogeneity of MicroRNA Expression in Rectal Cancer

    OpenAIRE

    Anne Haahr Mellergaard Eriksen; Rikke Fredslund Andersen; Boye Schnack Nielsen; Flemming Brandt Sørensen; Ane Lindegaard Appelt; Anders Jakobsen; Torben Frøstrup Hansen

    2016-01-01

    Introduction An increasing number of studies have investigated microRNAs (miRNAs) as potential markers of diagnosis, treatment and prognosis. So far, agreement between studies has been minimal, which may in part be explained by intratumoral heterogeneity of miRNA expression. The aim of the present study was to assess the heterogeneity of a panel of selected miRNAs in rectal cancer, using two different technical approaches. Materials and Methods The expression of the investigated miRNAs was an...

  5. Quantitative Chemical-Genetic Interaction Map Connects Gene Alterations to Drug Responses | Office of Cancer Genomics

    Science.gov (United States)

    In a recent Cancer Discovery report, CTD2 researchers at the University of California in San Francisco developed a new quantitative chemical-genetic interaction mapping approach to evaluate drug sensitivity or resistance in isogenic cell lines. Performing a high-throughput screen with isogenic cell lines allowed the researchers to explore the impact of a panel of emerging and established drugs on cells overexpressing a single cancer-associated gene in isolation.

  6. Altered subjective reward valuation among drug-deprived heavy marijuana users: Aversion to uncertainty

    OpenAIRE

    Hefner, Kathryn R.; Starr, Mark. J.; Curtin, John J.

    2015-01-01

    Marijuana is the most commonly used illicit drug in the United States and its use is rising. Nonetheless, scientific efforts to clarify the risk for addiction and other harm associated with marijuana use have been lacking. Maladaptive decision-making is a cardinal feature of addiction that is likely to emerge in heavy users. In particular, distorted subjective reward valuation related to homeostatic or allostatic processes has been implicated for many drugs of abuse. Selective changes in resp...

  7. P-glycoprotein alters blood–brain barrier penetration of antiepileptic drugs in rats with medically intractable epilepsy

    Directory of Open Access Journals (Sweden)

    Ma A

    2013-12-01

    Full Text Available Aimei Ma,1,* Cuicui Wang,2,3,* Yinghui Chen,2,3 Weien Yuan4 1Department of Neurology, The People's Hospital of Shanxi Province, Taiyuan, 2Department of Neurology, Jinshan Hospital, Fudan University, 3Department of Neurology, Shanghai Medical College, Shanghai, 4School of Pharmacy, Shanghai JiaoTong University, Shanghai, People's Republic of China *These authors contributed equally to this work Abstract: P-glycoprotein is one of the earliest known multidrug transporters and plays an important role in resistance to chemotherapeutic drugs. In this study, we detected levels of P-glycoprotein and its mRNA expression in a rat brain model of medically intractable epilepsy established by amygdala kindling and drug selection. We investigated whether inhibition of P-glycoprotein affects the concentration of antiepileptic drugs in cortical extracellular fluid. We found that levels of P-glycoprotein and its mRNA expression were upregulated in epileptic cerebral tissue compared with cerebral tissue from normal rats. The concentrations of two antiepileptic drugs, carbamazepine and phenytoin, were very low in the cortical extracellular fluid of rats with medically intractable epilepsy, and were restored after blockade of P-glycoprotein by verapamil. These results show that increased P-glycoprotein levels alter the ability of carbamazepine and phenytoin to penetrate the blood–brain barrier and reduce the concentrations of these agents in extracellular cortical fluid. High P-glycoprotein levels may be involved in resistance to antiepileptic drugs in medically intractable epilepsy. Keywords: P-glycoprotein, medically intractable epilepsy, antiepileptic drugs, amygdala kindling, verapamil

  8. Genomic alterations in BCL2L1 and DLC1 contribute to drug sensitivity in gastric cancer.

    Science.gov (United States)

    Park, Hansoo; Cho, Sung-Yup; Kim, Hyerim; Na, Deukchae; Han, Jee Yun; Chae, Jeesoo; Park, Changho; Park, Ok-Kyoung; Min, Seoyeon; Kang, Jinjoo; Choi, Boram; Min, Jimin; Kwon, Jee Young; Suh, Yun-Suhk; Kong, Seong-Ho; Lee, Hyuk-Joon; Liu, Edison T; Kim, Jong-Il; Kim, Sunghoon; Yang, Han-Kwang; Lee, Charles

    2015-10-01

    Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. Recent high-throughput analyses of genomic alterations revealed several driver genes and altered pathways in GC. However, therapeutic applications from genomic data are limited, largely as a result of the lack of druggable molecular targets and preclinical models for drug selection. To identify new therapeutic targets for GC, we performed array comparative genomic hybridization (aCGH) of DNA from 103 patients with GC for copy number alteration (CNA) analysis, and whole-exome sequencing from 55 GCs from the same patients for mutation profiling. Pathway analysis showed recurrent alterations in the Wnt signaling [APC, CTNNB1, and DLC1 (deleted in liver cancer 1)], ErbB signaling (ERBB2, PIK3CA, and KRAS), and p53 signaling/apoptosis [TP53 and BCL2L1 (BCL2-like 1)] pathways. In 18.4% of GC cases (19/103), amplification of the antiapoptotic gene BCL2L1 was observed, and subsequently a BCL2L1 inhibitor was shown to markedly decrease cell viability in BCL2L1-amplified cell lines and in similarly altered patient-derived GC xenografts, especially when combined with other chemotherapeutic agents. In 10.9% of cases (6/55), mutations in DLC1 were found and were also shown to confer a growth advantage for these cells via activation of Rho-ROCK signaling, rendering these cells more susceptible to a ROCK inhibitor. Taken together, our study implicates BCL2L1 and DLC1 as potential druggable targets for specific subsets of GC cases. PMID:26401016

  9. Altered subjective reward valuation among drug-deprived heavy marijuana users: Aversion to uncertainty.

    Science.gov (United States)

    Hefner, Kathryn R; Starr, Mark J; Curtin, John J

    2016-01-01

    Marijuana is the most commonly used illicit drug in the United States and its use is rising. Nonetheless, scientific efforts to clarify the risk for addiction and other harm associated with marijuana use have been lacking. Maladaptive decision-making is a cardinal feature of addiction that is likely to emerge in heavy users. In particular, distorted subjective reward valuation related to homeostatic or allostatic processes has been implicated for many drugs of abuse. Selective changes in responses to uncertainty have been observed in response to intoxication and deprivation from various drugs of abuse. To assess for these potential neuroadaptive changes in reward valuation associated with marijuana deprivation, we examined the subjective value of uncertain and certain rewards among deprived and nondeprived heavy marijuana users in a behavioral economics decision-making task. Deprived users displayed reduced valuation of uncertain rewards, particularly when these rewards were more objectively valuable. This uncertainty aversion increased with increasing quantity of marijuana use. These results suggest comparable decision-making vulnerability from marijuana use as other drugs of abuse, and highlights targets for intervention. PMID:26595464

  10. Altered Cell Cycle Arrest by Multifunctional Drug-Loaded Enzymatically-Triggered Nanoparticles.

    Science.gov (United States)

    Huang, Can; Sun, Ying; Shen, Ming; Zhang, Xiangyu; Gao, Pei; Duan, Yourong

    2016-01-20

    cRGD-targeting matrix metalloproteinase (MMP)-sensitive nanoparticles [PLGA-PEG1K-cRGD/PLGA-peptide-PEG5K (NPs-cRGD)] were successfully developed. Au-Pt(IV) nanoparticles, PTX, and ADR were encapsulated into NPs-RGD separately. The effects of the drug-loaded nanoparticles on the cell cycle were investigated. Here, we showed that higher cytotoxicity of drug-loaded nanoparticles was related to the cell cycle arrest, compared to that of free drugs. The NPs-cRGD studied here did not disrupt cell cycle progression. The cell cycle of Au-Pt(IV)@NPs-cRGD showed a main S phase arrest in all phases of the cell cycle phase, especially in G0/G1 phase. PTX@NPs-cRGD and ADR@NPs-cRGD showed a higher ratio of G2/M and S phase arrest than the free drugs, respectively. Cells in G0/G1 and S phases of the cell cycle had a higher uptake ratio of NPs-cRGD. A nutrient deprivation or an increase in the requirement of nutrients in tumor cells could promote the uptake of nanoparticles from the microenvironments. In vivo, NPs-cRGD could efficiently accumulate at tumor sites. The inhibition of tumor growth coupled with cell cycle arrest is in line with that in vitro. On the basis of our results, we propose that future studies on nanoparticle action mechanism should consider the cell cycle, which could be different from free drugs. Understanding the actions of cell cycle arrest could affect the application of nanomedicine in the clinic.

  11. Using C. elegans to screen for targets of ethanol and behavior-altering drugs

    Directory of Open Access Journals (Sweden)

    Davies Andrew G.

    2004-01-01

    Full Text Available Caenorhabditis elegans is an attractive model system for determining the targets of neuroactive compounds. Genetic screens in C. elegans provide a relatively unbiased approach to the identification of genes that are essential for behavioral effects of drugs and neuroactive compounds such as alcohol. Much work in vertebrate systems has identified multiple potential targets of ethanol but which, if any, of those candidates are responsible for the behavioral effects of alcohol is uncertain. Here we provide detailed methodology for a genetic screen for mutants of C. elegans that are resistant to the depressive effects of ethanol on locomotion and for the subsequent behavioral analysis of those mutants. The methods we describe should also be applicable for use in screening for mutants that are resistant or hypersensitive to many neuroactive compounds and for identifying the molecular targets or biochemical pathways mediating drug responses.

  12. Two-Step Delivery: Exploiting the Partition Coefficient Concept to Increase Intratumoral Paclitaxel Concentrations In vivo Using Responsive Nanoparticles

    Science.gov (United States)

    Colby, Aaron H.; Liu, Rong; Schulz, Morgan D.; Padera, Robert F.; Colson, Yolonda L.; Grinstaff, Mark W.

    2016-01-01

    Drug dose, high local target tissue concentration, and prolonged duration of exposure are essential criteria in achieving optimal drug performance. However, systemically delivered drugs often fail to effectively address these factors with only fractions of the injected dose reaching the target tissue. This is especially evident in the treatment of peritoneal cancers, including mesothelioma, ovarian, and pancreatic cancer, which regularly employ regimens of intravenous and/or intraperitoneal chemotherapy (e.g., gemcitabine, cisplatin, pemetrexed, and paclitaxel) with limited results. Here, we show that a “two-step” nanoparticle (NP) delivery system may address this limitation. This two-step approach involves the separate administration of NP and drug where, first, the NP localizes to tumor. Second, subsequent administration of drug then rapidly concentrates into the NP already stationed within the target tissue. This two-step method results in a greater than 5-fold increase in intratumoral drug concentrations compared to conventional “drug-alone” administration. These results suggest that this unique two-step delivery may provide a novel method for increasing drug concentrations in target tissues.

  13. Intratumoral diversity of telomere length in individual neuroblastoma tumors.

    Science.gov (United States)

    Pezzolo, Annalisa; Pistorio, Angela; Gambini, Claudio; Haupt, Riccardo; Ferraro, Manuela; Erminio, Giovanni; De Bernardi, Bruno; Garaventa, Alberto; Pistoia, Vito

    2015-04-10

    The purpose of the work was to investigate telomere length (TL) and mechanisms involved in TL maintenance in individual neuroblastoma (NB) tumors. Primary NB tumors from 102 patients, ninety Italian and twelve Spanish, diagnosed from 2000 to 2008 were studied. TL was investigated by quantitative fluorescence in situ hybridization (IQ-FISH) that allows to analyze individual cells in paraffin-embedded tissues. Fluorescence intensity of chromosome 2 centromere was used as internal control to normalize TL values to ploidy. Human telomerase reverse transcriptase (hTERT) expression was detected by immunofluorescence in 99/102 NB specimens.The main findings are the following: 1) two intratumoral subpopulations of cancer cells displaying telomeres of different length were identified in 32/102 tumors belonging to all stages. 2) hTERT expression was detected in 99/102 tumors, of which 31 displayed high expression and 68 low expression. Alternative lengthening of telomeres (ALT)-mechanism was present in 60/102 tumors, 20 of which showed high hTERT expression. Neither ALT-mechanism nor hTERT expression correlated with heterogeneous TL. 3) High hTERT expression and ALT positivity were associated with significantly reduced Overall Survival. 4) High hTERT expression predicted relapse irrespective of patient age. Intratumoral diversity in TL represents a novel feature in NB.In conclusion, diversity of TL in individual NB tumors was strongly associated with disease progression and death, suggesting that these findings are of translational relevance. The combination of high hTERT expression and ALT positivity may represent a novel biomarker of poor prognosis that deserves further investigation. PMID:25595889

  14. Does respondent driven sampling alter the social network composition and health-seeking behaviors of illicit drug users followed prospectively?

    Directory of Open Access Journals (Sweden)

    Abby E Rudolph

    Full Text Available Respondent driven sampling (RDS was originally developed to sample and provide peer education to injection drug users at risk for HIV. Based on the premise that drug users' social networks were maintained through sharing rituals, this peer-driven approach to disseminate educational information and reduce risk behaviors capitalizes and expands upon the norms that sustain these relationships. Compared with traditional outreach interventions, peer-driven interventions produce greater reductions in HIV risk behaviors and adoption of safer behaviors over time, however, control and intervention groups are not similarly recruited. As peer-recruitment may alter risk networks and individual risk behaviors over time, such comparison studies are unable to isolate the effect of a peer-delivered intervention. This analysis examines whether RDS recruitment (without an intervention is associated with changes in health-seeking behaviors and network composition over 6 months. New York City drug users (N = 618 were recruited using targeted street outreach (TSO and RDS (2006-2009. 329 non-injectors (RDS = 237; TSO = 92 completed baseline and 6-month surveys ascertaining demographic, drug use, and network characteristics. Chi-square and t-tests compared RDS- and TSO-recruited participants on changes in HIV testing and drug treatment utilization and in the proportion of drug using, sex, incarcerated and social support networks over the follow-up period. The sample was 66% male, 24% Hispanic, 69% black, 62% homeless, and the median age was 35. At baseline, the median network size was 3, 86% used crack, 70% used cocaine, 40% used heroin, and in the past 6 months 72% were tested for HIV and 46% were enrolled in drug treatment. There were no significant differences by recruitment strategy with respect to changes in health-seeking behaviors or network composition over 6 months. These findings suggest no association between RDS recruitment and changes in

  15. Understanding Intratumoral Heterogeneity: Lessons from the Analysis of At-Risk Tissue and Premalignant Lesions in the Colon.

    Science.gov (United States)

    Sievers, Chelsie K; Leystra, Alyssa A; Clipson, Linda; Dove, William F; Halberg, Richard B

    2016-08-01

    Advances in DNA sequencing have created new opportunities to better understand the biology of cancers. Attention is currently focused on precision medicine: does a cancer carry a mutation that is targetable with already available drugs? But, the timing at which multiple, targetable mutations arise during the adenoma to carcinoma sequence remains unresolved. Borras and colleagues identified mutations and allelic imbalance in at-risk mucosa and early polyps in the human colon. Their analyses indicate that mutations in key genes can arise quite early during tumorigenesis and that polyps are often multiclonal with at least two clones. These results are consistent with the "Big Bang" model of tumorigenesis, which postulates that intratumoral heterogeneity is a consequence of a mutational burst in the first few cell divisions following initiation that drives divergence from a single founder with unique but related clones coevolving. Emerging questions center around the ancestry of the tumor and impact of early intratumoral heterogeneity on tumor establishment, growth, progression, and most importantly, response to therapeutic intervention. Additional sequencing studies in which samples, especially at-risk tissue and premalignant neoplasms, are analyzed from animal models and humans will further our understanding of tumorigenesis and lead to more effective strategies for prevention and treatment. Cancer Prev Res; 9(8); 638-41. ©2016 AACRSee related article by Borras, et al., Cancer Prev Res 2016;9(6):417-427. PMID:27199343

  16. Photodynamic Therapy Induced Enhancement of Tumor Vasculature Permeability Using an Upconversion Nanoconstruct for Improved Intratumoral Nanoparticle Delivery in Deep Tissues

    Science.gov (United States)

    Gao, Weidong; Wang, Zhaohui; Lv, Liwei; Yin, Deyan; Chen, Dan; Han, Zhihao; Ma, Yi; Zhang, Min; Yang, Man; Gu, Yueqing

    2016-01-01

    Photodynamic therapy (PDT) has recently emerged as an approach to enhance intratumoral accumulation of nanoparticles. However, conventional PDT is greatly limited by the inability of the excitation light to sufficiently penetrate tissue, rendering PDT ineffective in the relatively deep tumors. To address this limitation, we developed a novel PDT platform and reported for the first time the effect of deep-tissue PDT on nanoparticle uptake in tumors. This platform employed c(RGDyK)-conjugated upconversion nanoparticles (UCNPs), which facilitate active targeting of the nanoconstruct to tumor vasculature and achieve the deep-tissue photosensitizer activation by NIR light irradiation. Results indicated that our PDT system efficiently enhanced intratumoral uptake of different nanoparticles in a deep-seated tumor model. The optimal light dose for deep-tissue PDT (34 mW/cm2) was determined and the most robust permeability enhancement was achieved by administering the nanoparticles within 15 minutes following PDT treatment. Further, a two-step treatment strategy was developed and validated featuring the capability of improving the therapeutic efficacy of Doxil while simultaneously reducing its cardiotoxicity. This two-step treatment resulted in a tumor inhibition rate of 79% compared with 56% after Doxil treatment alone. These findings provide evidence in support of the clinical application of deep-tissue PDT for enhanced nano-drug delivery. PMID:27279907

  17. Genetic diversity in normal cell populations is the earliest stage of oncogenesis leading to intra-tumor heterogeneity

    Directory of Open Access Journals (Sweden)

    Cory L Howk

    2013-04-01

    Full Text Available Random mutations and epigenetic alterations provide a rich substrate for microevolutionary phenomena to occur in proliferating epithelial tissues. Genetic diversity resulting from random mutations in normal cells is critically important for understanding the genetic basis of oncogenesis. However, evaluation of the cell-specific role of individual (epi-genetic alterations in living tissues is extremely difficult from a direct experimental perspective. We have developed a theoretical model for uterine epithelial cell proliferation. Computational simulations have shown that a base-line mutation rate of two mutations per cell division is sufficient to explain sporadic endometrial cancer as a rare evolutionary consequence with an incidence similar to that reported in SEER data. Simulation of the entire oncogenic process has allowed us to analyze the features of the tumor initiating cells and their clonal expansion. Analysis of the malignant features of individual cancer cells, such as de-differentiation status, proliferation potential, and immortalization status, permits a mathematical characterization of malignancy and a comparison of intra-tumor heterogeneity between individual tumors. We found, under the conditions specified, that cancer stem cells account for approximately 7% of the total cancer cell population. Taken together, our mathematical modeling describes the genetic diversity and evolution in a normal cell population at the early stages of oncogenesis and characterizes intra-tumor heterogeneity. This model has explored the role of accumulation of a large number of genetic alterations in oncogenesis as an alternative to traditional biological approaches emphasizing the driving role of a small number of genetic mutations, and this accumulation, along with environmental factors, has a significant impact on the growth advantage of and selection pressure on individual cancer cells and the resulting tumor composition and progression.

  18. Does the appearance of drug resistance during therapy alter bacterial susceptibility to opsonophagocytosis?

    Science.gov (United States)

    Gemmell, C G

    1996-01-01

    Coagulase-negative staphylococci (CNS) are common causes of infection in patients undergoing chronic ambulatory peritoneal dialysis (CAPD). Their ability to survive intracellularly within peritoneal macrophages and to persist within the peritoneum during antibiotic therapy has led to the development of drug resistance during treatment. Strains of Staphylococcus epidermidis (SE) and Staphytococcus haemolyticus (SH) have been isolated from patients with CAPD during treatment with ciprofloxacin. The respective MIC values pre-and post-therapy were SE-0.25 and 128 mg/L and SH-0.50 and 64 mg/L. The susceptibility of each isolate to opsonophagocytosis was measured in vitro using isolated polymorphonuclear leucocytes (PMN) derived from fresh human blood donations. The bacteria were radiolabelled during growth, opsonised in either 1 or 10% serum and their uptake measured No differences were seen between the pre- and post therapy isolates when using 10% serum as opsonic source (18 vs. 21%); with 1% serum the corresponding values were lower (5 and 8% respectively). Similarly their ability to generate a respiratory burst as measured by chemiluminescence (CL) in the phagocytic cells was not diminished in the strains which had developed resistance to ciprofloxacin. The mean CL response to the strains isolated at outset of therapy ranged from 0.35-0.45 cpsc, and to the resistant strains following therapy from 0.36-0.50 cpsc. It is clear from the present investigation that although the bacterial strain became at least 10 times more resistant to ciprofloxacin during therapy, no change in their susceptibility to phagocytosis occurred refuting the idea that the emergence of drug resistant strains during therapy results in "super-bugs" of greater virulence.

  19. Effect of milk hydrolysates on inflammation markers and drug-induced transcriptional alterations in cell-based models

    DEFF Research Database (Denmark)

    Nielsen, Ditte Søvsø Gundelund; Theil, Peter Kappel; Larsen, Lotte Bach;

    2012-01-01

    Nonsteroidal anti-inflammatory drugs (NSAID) are associated with gastrointestinal inflammation and subsequent damage to the intestinal tissue. Earlier studies in our laboratory have found that specific casein hydrolysates (CH) might be useful in the treatment of gastrointestinal wounds....... The underlying mechanisms that support inflammation and wound healing are not completely understood, but transcriptional alterations may be used as markers for inflammation and wound healing. The bioactivity of 3 CH prepared by treatment of commercial casein with pepsin (60 min) followed by corolase (0, 10......B (NFκB) by real-time PCR. Furthermore, the effect of CH on lipopolysaccharide-induced inflammation was evaluated in macrophages by measuring PG E2 levels. Casein hydrolysates treated with corolase for 10 or 60 min after pepsin treatment downregulated transcription of TGF-β1 and NFκB (P

  20. Doxorubicin-induced co-assembling nanomedicines with temperature-sensitive acidic polymer and their in-situ-forming hydrogels for intratumoral administration.

    Science.gov (United States)

    Wan, Jiangshan; Geng, Shinan; Zhao, Hao; Peng, Xiaole; Zhou, Qing; Li, Han; He, Ming; Zhao, Yanbing; Yang, Xiangliang; Xu, Huibi

    2016-08-10

    Doxorubicin (DOX)-induced co-assembling nanomedicines (D-PNAx) with temperature-sensitive PNAx triblock polymers have been developed for regional chemotherapy against liver cancer via intratumoral administration in the present work. Owing to the formation of insoluble DOX carboxylate, D-PNAx nanomedicines showed high drug-loading and entrapment efficacy via a simple mixing of doxorubicin hydrochloride and PNAx polymers. The sustained releasing profile of D-PNA100 nanomedicines indicated that only 9.4% of DOX was released within 1day, and 60% was released during 10days. Based on DOX-induced co-assembling behavior and their temperature sensitive in-situ-forming hydrogels, D-PNA100 nanomedicines showed excellent antitumor activity against H22 tumor using intratumoral administration. In contrast to that by free DOX solution (1.13±0.04 times at 9days) and blank PNA100 (2.11±0.34 times), the tumor volume treated by D-PNA100 had been falling to only 0.77±0.13 times of original tumor volume throughout the experimental period. In vivo biodistribution of DOX indicated that D-PNA100 nanomedicines exhibited much stronger DOX retention in tumor tissues than free DOX solution via intratumoral injection. D-PNA100 nanomedicines were hopeful to be developed as new temperature sensitive in-situ-forming hydrogels via i.t. injection for regional chemotherapy. PMID:27282415

  1. Altering Antibody-Drug Conjugate Binding to the Neonatal Fc Receptor Impacts Efficacy and Tolerability.

    Science.gov (United States)

    Hamblett, Kevin J; Le, Tiep; Rock, Brooke M; Rock, Dan A; Siu, Sophia; Huard, Justin N; Conner, Kip P; Milburn, Robert R; O'Neill, Jason W; Tometsko, Mark E; Fanslow, William C

    2016-07-01

    Antibody-drug conjugates (ADC) rely on the target-binding specificity of an antibody to selectively deliver potent drugs to cancer cells. IgG antibody half-life is regulated by neonatal Fc receptor (FcRn) binding. Histidine 435 of human IgG was mutated to alanine (H435A) to explore the effect of FcRn binding on the pharmacokinetics, efficacy, and tolerability of two separate maytansine-based ADC pairs with noncleavable linkers, (c-DM1 and c-H435A-DM1) and (7v-Cys-may and 7v-H435A-Cys-may). The in vitro cell-killing potency of each pair of ADCs was similar, demonstrating that H435A showed no measurable impact on ADC bioactivity. The H435A mutant antibodies showed no detectable binding to human or mouse FcRn in vitro, whereas their counterpart wild-type IgG ADCs were found to bind to FcRn at pH = 6.0. In xenograft bearing SCID mice expressing mouse FcRn, the AUC of 7v-Cys-may was 1.6-fold higher than that of 7v-H435A-may, yet the observed efficacy was similar. More severe thrombocytopenia was observed with 7v-H435A-Cys-may as compared to 7v-Cys-may at multiple dose levels. The AUC of c-DM1 was approximately 3-fold higher than that of c-H435A-DM1 in 786-0 xenograft bearing SCID mice, which led to a 3-fold difference in efficacy by dose. Murine FcRn knockout, human FcRn transgenic line 32 SCID animals bearing 786-0 xenografts showed an amplified exposure difference between c-DM1 and c-H435A-DM1 as compared to murine FcRn expressing SCID mice, leading to a 10-fold higher dose required for efficacy despite a 6-fold higher AUC of the c-H435A-DM1. The accelerated clearance observed for the noncleavable maytansine ADCs with the H435A FcRn mutation led to reduced efficacy at equivalent doses and exacerbation of clinical pathology parameters (decreased tolerability) at equivalent doses. The results show that reduced ADC clearance mediated by FcRn modulation can improve therapeutic index. PMID:27248573

  2. Sexual differentiation of the brain: a model for drug-induced alterations of the reproductive system

    International Nuclear Information System (INIS)

    The process of the sexual differentiation of the brain represents a valuable model system for the study of the chemical modification of the mammalian brain. Although there are numerous functional and structural sex differences in the adult brain, these are imposed on an essentially feminine or bipotential brain by testicular hormones during a critical phase of perinatal development in the rat. It is suggested that a relatively marked structural sex difference in the rat brain, the sexually dimorphic nucleus of the preoptic area (SDN-POA), is a morphological signature of the permanent or organizational action of estradiol derived from the aromatization of testicular testosterone. The SDN-POA of the male rat is severalfold larger in volume and is composed of more neurons than that of the female. The observation that the mitotic formation of the neurons of the SDN-POA is specifically prolonged has enabled us to identify the time course and pathway of neuronal migration into the nucleus. Study of the development of the SDN-POA suggests that estradiol in the male increases the number of neurons which survive a phase of neuronal death by exerting a neurite growth promoting action and/or a direct neuronotrophic action. Finally, although it is clear that gonadal hormones have dramatic permanent effects on the brain during perinatal development, even after puberty and in adulthood gonadal steroids can alter neuronal structure and, perhaps as a corollary to this, have permanent effects on reproductive function. Although the brain may be most sensitive to gonadal hormones or exogenous chemical factors during perinatal development, such as sensitivity does not appear limited to this period

  3. A Surface Biotinylation Strategy for Reproducible Plasma Membrane Protein Purification and Tracking of Genetic and Drug-Induced Alterations.

    Science.gov (United States)

    Hörmann, Katrin; Stukalov, Alexey; Müller, André C; Heinz, Leonhard X; Superti-Furga, Giulio; Colinge, Jacques; Bennett, Keiryn L

    2016-02-01

    Plasma membrane (PM) proteins contribute to the identity of a cell, mediate contact and communication, and account for more than two-thirds of known drug targets.1-8 In the past years, several protocols for the proteomic profiling of PM proteins have been described. Nevertheless, comparative analyses have mainly focused on different variations of one approach.9-11 We compared sulfo-NHS-SS-biotinylation, aminooxy-biotinylation, and surface coating with silica beads to isolate PM proteins for subsequent analysis by one-dimensional gel-free liquid chromatography mass spectrometry. Absolute and relative numbers of PM proteins and reproducibility parameters on a qualitative and quantitative level were assessed. Sulfo-NHS-SS-biotinylation outperformed aminooxy-biotinylation and surface coating using silica beads for most of the monitored criteria. We further simplified this procedure by a competitive biotin elution strategy achieving an average PM annotated protein fraction of 54% (347 proteins). Computational analysis using additional databases and prediction tools revealed that in total over 90% of the purified proteins were associated with the PM, mostly as interactors. The modified sulfo-NHS-SS-biotinylation protocol was validated by tracking changes in the plasma membrane proteome composition induced by genetic alteration and drug treatment. Glycosylphosphatidylinositol (GPI)-anchored proteins were depleted in PM purifications from cells deficient in the GPI transamidase component PIGS, and treatment of cells with tunicamycin significantly reduced the abundance of N-glycoproteins in surface purifications.

  4. DREAMing: a simple and ultrasensitive method for assessing intratumor epigenetic heterogeneity directly from liquid biopsies.

    Science.gov (United States)

    Pisanic, Thomas R; Athamanolap, Pornpat; Poh, Weijie; Chen, Chen; Hulbert, Alicia; Brock, Malcolm V; Herman, James G; Wang, Tza-Huei

    2015-12-15

    Many cancers comprise heterogeneous populations of cells at primary and metastatic sites throughout the body. The presence or emergence of distinct subclones with drug-resistant genetic and epigenetic phenotypes within these populations can greatly complicate therapeutic intervention. Liquid biopsies of peripheral blood from cancer patients have been suggested as an ideal means of sampling intratumor genetic and epigenetic heterogeneity for diagnostics, monitoring and therapeutic guidance. However, current molecular diagnostic and sequencing methods are not well suited to the routine assessment of epigenetic heterogeneity in difficult samples such as liquid biopsies that contain intrinsically low fractional concentrations of circulating tumor DNA (ctDNA) and rare epigenetic subclonal populations. Here we report an alternative approach, deemed DREAMing (Discrimination of Rare EpiAlleles by Melt), which uses semi-limiting dilution and precise melt curve analysis to distinguish and enumerate individual copies of epiallelic species at single-CpG-site resolution in fractions as low as 0.005%, providing facile and inexpensive ultrasensitive assessment of locus-specific epigenetic heterogeneity directly from liquid biopsies. The technique is demonstrated here for the evaluation of epigenetic heterogeneity at p14(ARF) and BRCA1 gene-promoter loci in liquid biopsies obtained from patients in association with non-small cell lung cancer (NSCLC) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN), respectively.

  5. Androgen deprivation promotes intratumoral synthesis of dihydrotestosterone from androgen metabolites in prostate cancer

    OpenAIRE

    Fumio Ishizaki; Tsutomu Nishiyama; Takashi Kawasaki; Yoshimichi Miyashiro; Noboru Hara; Itsuhiro Takizawa; Makoto Naito; Kota Takahashi

    2013-01-01

    Intratumoral synthesis of dihydrotestosterone (DHT) from precursors cannot completely explain the castration resistance of prostate cancer. We showed that DHT was intratumorally synthesized from the inactive androgen metabolites 5α-androstane-3α/β,17β-diol (3α/β-diol) in prostate cancer cells via different pathways in a concentration-dependent manner. Additionally, long-term culture in androgen-deprived media increased transcriptomic expression of 17β-hydroxysteroid dehydrogenase type 6 (HSD1...

  6. Intratumoral steroidogenesis in castration-resistant prostate cancer: a target for therapy

    OpenAIRE

    Armandari, Inna; Hamid, Agus Rizal; Verhaegh, Gerald; Schalken, Jack

    2014-01-01

    Development of castration-resistant prostate cancer (CRPC) in a low androgen environment, arising from androgen deprivation therapy (ADT), is a major problem in patients with advanced prostate cancer (PCa). Several mechanisms have been hypothesized to explain the progression of PCa to CRPC during ADT, one of them is so called persistent intratumoral steroidogenesis. The existence of intratumoral steroidogenesis was hinted based on the residual levels of intraprostatic testosterone (T) and dih...

  7. Intratumoral hemorrhage in a patient with cerebellar hemangioblastoma: a case report and review.

    Science.gov (United States)

    Wang, Zhen; Hu, Jun; Xu, Liang; Malaguit, Jay; Chen, Sheng

    2015-01-01

    Spontaneous hemorrhage is rarely associated with hemangioblastomas. Intratumoral hemorrhage occurring in cerebellar hemangioblastomas is more rare. A 25-year-old man was admitted to our hospital with headache. We found a round cystic lesion with solid part in the right cerebellum. The lesion was resected. The final pathological diagnosis was hemangioblastomas. The radiological features of this case were similar to normal hemangioblastomas, whereas our histological examination showed the occurrence of the intratumoral hemorrhage. If the hemangioblastoma ruptures in our case, the outcome of the patient will be worse. It is difficult to identify the intratumoral hemorrhage of hemangioblastomas and quite dangerous if it is diagnosed late. Diagnosing an intratumoral hemorrhage of hemangioblastomas still needs a further discussion. Genetic screening may help us make an early diagnosis. Furthermore, the mechanism about intratumoral hemorrhage of hemangioblastomas remains unknown. The mutation of D6Mit135 gene on chromosome 6 may be responsible for the vascular dilation and hemorrhage induction in the hemangioblastomas. Tumor size, upregulation of vascular endothelial growth factor, spinalradicular location, and solid type are also factors relating to the hemorrhage of hemangioblastomas. The purpose of reporting our case is 2-fold: to remind clinicians to consider the possibility of internal hemorrhaging while diagnosing this disease, and provide a starting point to discuss mechanisms regarding the intratumoral hemorrhage of hemangioblastomas. PMID:25634201

  8. Long-term alterations in vulnerability to addiction to drugs of abuse and in brain gene expression after early life ethanol exposure.

    Science.gov (United States)

    Barbier, Estelle; Pierrefiche, Olivier; Vaudry, David; Vaudry, Hubert; Daoust, Martine; Naassila, Mickaël

    2008-12-01

    Exposure to ethanol early in life can have long-lasting implications on brain function and drug of abuse response later in life. The present study investigated in rats, the long-term consequences of pre- and postnatal (early life) ethanol exposure on drug consumption/reward and the molecular targets potentially associated with these behavioral alterations. Since a relationship has been demonstrated between heightened drugs intake and susceptibility to drugs-induced locomotor activity/sensitization, anxiolysis, we tested these behavioral responses, depending on the drug, in control and early life ethanol-exposed animals. Our results show that progeny exposed to early life ethanol displayed increased consumption of ethanol solutions and increased sensitivity to cocaine rewarding effects assessed in the conditioned place preference test. Offspring exposed to ethanol were more sensitive to the anxiolytic effect of ethanol and the increased sensitivity could, at least in part, explain the alteration in the consumption of ethanol for its anxiolytic effects. In addition, the sensitivity to hypothermic effects of ethanol and ethanol metabolism were not altered by early life ethanol exposure. The sensitization to cocaine (20 mg/kg) and to amphetamine (1.2 mg/kg) was increased after early life ethanol exposure and, could partly explain, an increase in the rewarding properties of psychostimulants. Gene expression analysis revealed that expression of a large number of genes was altered in brain regions involved in the reinforcing effects of drugs of abuse. Dopaminergic receptors and transporter binding sites were also down-regulated in the striatum of ethanol-exposed offspring. Such long-term neurochemical alterations in transmitter systems and in the behavioral responses to ethanol and other drugs of abuse may confer an increased liability for addiction in exposed offspring. PMID:18713641

  9. Intratumoral distribution of EGFR-amplified and EGFR-mutated cells in pulmonary adenocarcinoma.

    Science.gov (United States)

    Soma, Shingo; Tsuta, Koji; Takano, Toshimi; Hatanaka, Yutaka; Yoshida, Akihiko; Suzuki, Kenji; Asamura, Hisao; Tsuda, Hitoshi

    2014-03-01

    Alterations in the epidermal growth factor receptor (EGFR) gene are associated with carcinogenesis in non-small cell lung cancer. However, the intratumoral distribution of these abnormalities has not been elucidated. This study included patients with surgically resected lung adenocarcinoma. The predominant histological growth pattern was determined. Chromogenic in situ hybridization (CISH) and EGFR-mutation specific-antibodies were used for analysis of changes in gene copy number and EGFR mutations, respectively. EGFR mutation detected immunohistochemistry (IHC) and amplification were identified in 31 (53%) and 30 (52%) cases, respectively. The predominant growth patterns in the 58 tumors evaluated were papillary (28, 48%), lepidic (8, 14%), acinar (15, 26%), and solid (7, 12%). EGFR mutations were the least common in cases with a solid predominant pattern. The incidence of EGFR amplification did not differ among predominant patterns. Analyzing each histological subtype, no differences were noted between the prevalence of EGFR-IHC positive and CISH-positive rates. In the analysis of EGFR amplification, CISH-positive status was more prevalent in IHC-positive cases than in IHC-negative cases. All 19 cases that were both IHC and CISH positive were analyzed. In 17 cases (90%), the IHC-positive area was equal to or larger than the CISH-positive area. Among the histological subtypes of lung adenocarcinoma, the solid predominant subtype was distinguishable by its infrequent EGFR mutations. EGFR gene mutations preceded changes in oncogenic drive, more so than did EGFR gene number alterations during the developmental process of lung adenocarcinoma. PMID:24355440

  10. Whole genome sequence analysis suggests intratumoral heterogeneity in dissemination of breast cancer to lymph nodes.

    Directory of Open Access Journals (Sweden)

    Kevin Blighe

    Full Text Available BACKGROUND: Intratumoral heterogeneity may help drive resistance to targeted therapies in cancer. In breast cancer, the presence of nodal metastases is a key indicator of poorer overall survival. The aim of this study was to identify somatic genetic alterations in early dissemination of breast cancer by whole genome next generation sequencing (NGS of a primary breast tumor, a matched locally-involved axillary lymph node and healthy normal DNA from blood. METHODS: Whole genome NGS was performed on 12 µg (range 11.1-13.3 µg of DNA isolated from fresh-frozen primary breast tumor, axillary lymph node and peripheral blood following the DNA nanoball sequencing protocol. Single nucleotide variants, insertions, deletions, and substitutions were identified through a bioinformatic pipeline and compared to CIN25, a key set of genes associated with tumor metastasis. RESULTS: Whole genome sequencing revealed overlapping variants between the tumor and node, but also variants that were unique to each. Novel mutations unique to the node included those found in two CIN25 targets, TGIF2 and CCNB2, which are related to transcription cyclin activity and chromosomal stability, respectively, and a unique frameshift in PDS5B, which is required for accurate sister chromatid segregation during cell division. We also identified dominant clonal variants that progressed from tumor to node, including SNVs in TP53 and ARAP3, which mediates rearrangements to the cytoskeleton and cell shape, and an insertion in TOP2A, the expression of which is significantly associated with tumor proliferation and can segregate breast cancers by outcome. CONCLUSION: This case study provides preliminary evidence that primary tumor and early nodal metastasis have largely overlapping somatic genetic alterations. There were very few mutations unique to the involved node. However, significant conclusions regarding early dissemination needs analysis of a larger number of patient samples.

  11. Into the clinic: Talimogene laherparepvec (T-VEC), a first-in-class intratumoral oncolytic viral therapy.

    Science.gov (United States)

    Rehman, Hasan; Silk, Ann W; Kane, Michael P; Kaufman, Howard L

    2016-01-01

    With the recent regulatory approval of Talimogene laherparepvec (T-VEC) for the treatment of advanced of melanoma in the United States, Europe and Australia, oncolytic virus immunotherapy has earned its place in the clinic. However, the adoption of T-VEC by the U.S. oncology community has been slow, and so far has been largely limited to specialized cancer centers. Limiting factors include the intratumoral route of administration, which is unfamiliar to medical oncologists, biosafety concerns related to the use of a live virus in the clinic, and the explosion of other therapeutic strategies now available for the treatment of advanced melanoma. Herein, we review the development of T-VEC, and suggest how it fits into the in the current clinical treatment paradigm, and provide pearls for drug preparation, administration, and monitoring of response to therapy. PMID:27660707

  12. Intratumoral sampling variability in hepatocellular carcinoma: A case report

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The differential diagnosis between hepatocellular carcinoma (HCC) and regenerative liver nodules and other primary liver tumors may be very difficult,particularly when performed on liver biopsies. Difficulties in histological typing may be often minimized by immunohistochemistry. Among the numerous markers proposed, CK18, Hep Par1 and glypican 3 (GPC3) are considered the most useful in HCC diagnosis. Here we report a case of HCC in a 72-year-old male with HBV-related chronic liver disease, characterized by a marked morphological and immunohistochemical intratumoral variability. In this case, tumor grading ranged from areas extremely well differentiated, similar to regenerative nodule, to undifferentiated regions, with large atypical multinucleated cells. While almost all sub nodules were immunostained by Hep Par 1, immunoreactivity for glypican 3 and for Ck18 was patchy, with negative tumor region adjacent to the highly immunoreactive areas. Our case stresses the relevance of sampling variability in the diagnosis of HCC, and indicates that caution should be taken in grading an HCC and in the interpretation of immunohistochemical stains when only small core biopsies from liver nodules are available.

  13. Tertiary Intratumor Lymphoid Tissue in Colo-Rectal Cancer

    International Nuclear Information System (INIS)

    Ectopic (or tertiary) lymphoid tissue develops at sites of inflammation or infection in non lymphoid organs and is associated with chronic inflammation. In colon mucosa, small lymphoid aggregates are already present in homeostatic conditions, as part of the gut-associated lymphoid tissue and play an essential role in the immune response to perturbations of the mucosal microenvironment. Despite the recognized role of inflammation in tumor progression, the presence and biological function of lymphoid tissue in cancer has been poorly investigated. We identified aggregates of lymphocytes resembling tertiary lymphoid tissue in human colorectal cancer specimens; intratumor accumulations of lymphocytes display a high degree of compartmentalization, with B and T cells, mature dendritic cells and a network of CD21+ follicular dendritic cells (FDC). We analyzed the adaptation of colon lymphoid tissue in a murine model of colitis-associated cancer (AOM/DSS). B cell follicle formation increases in the context of the chronic inflammation associated to intestinal neoplasia, in this model. A network of lymphatic and haematic vessels surrounding B cell follicles is present and includes high endothelial venules (HEV). Future task is to determine whether lymphoid tissue contributes to the persistence of the tumor-associated inflammatory reaction, rather than represent a functional immune compartment, potentially participating to the anti tumor response

  14. Tertiary Intratumor Lymphoid Tissue in Colo-Rectal Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Bergomas, Francesca [Department of Immunology and Inflammation, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy); Grizzi, Fabio [Laboratory of Molecular Gastroenterology, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy); Doni, Andrea; Pesce, Samantha [Department of Immunology and Inflammation, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy); Laghi, Luigi [Laboratory of Molecular Gastroenterology, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy); Department of Gastroenterology, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy); Allavena, Paola [Department of Immunology and Inflammation, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy); Mantovani, Alberto [Department of Immunology and Inflammation, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy); Department of Translational Medicine, University of Milan, Milan 20089 (Italy); Marchesi, Federica, E-mail: federica.marchesi@humanitasresearch.it [Department of Immunology and Inflammation, IRCCS Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan (Italy)

    2011-12-28

    Ectopic (or tertiary) lymphoid tissue develops at sites of inflammation or infection in non lymphoid organs and is associated with chronic inflammation. In colon mucosa, small lymphoid aggregates are already present in homeostatic conditions, as part of the gut-associated lymphoid tissue and play an essential role in the immune response to perturbations of the mucosal microenvironment. Despite the recognized role of inflammation in tumor progression, the presence and biological function of lymphoid tissue in cancer has been poorly investigated. We identified aggregates of lymphocytes resembling tertiary lymphoid tissue in human colorectal cancer specimens; intratumor accumulations of lymphocytes display a high degree of compartmentalization, with B and T cells, mature dendritic cells and a network of CD21{sup +} follicular dendritic cells (FDC). We analyzed the adaptation of colon lymphoid tissue in a murine model of colitis-associated cancer (AOM/DSS). B cell follicle formation increases in the context of the chronic inflammation associated to intestinal neoplasia, in this model. A network of lymphatic and haematic vessels surrounding B cell follicles is present and includes high endothelial venules (HEV). Future task is to determine whether lymphoid tissue contributes to the persistence of the tumor-associated inflammatory reaction, rather than represent a functional immune compartment, potentially participating to the anti tumor response.

  15. Tertiary Intratumor Lymphoid Tissue in Colo-Rectal Cancer

    Directory of Open Access Journals (Sweden)

    Federica Marchesi

    2011-12-01

    Full Text Available Ectopic (or tertiary lymphoid tissue develops at sites of inflammation or infection in non lymphoid organs and is associated with chronic inflammation. In colon mucosa, small lymphoid aggregates are already present in homeostatic conditions, as part of the gut-associated lymphoid tissue and play an essential role in the immune response to perturbations of the mucosal microenvironment. Despite the recognized role of inflammation in tumor progression, the presence and biological function of lymphoid tissue in cancer has been poorly investigated. We identified aggregates of lymphocytes resembling tertiary lymphoid tissue in human colorectal cancer specimens; intratumor accumulations of lymphocytes display a high degree of compartmentalization, with B and T cells, mature dendritic cells and a network of CD21+ follicular dendritic cells (FDC. We analyzed the adaptation of colon lymphoid tissue in a murine model of colitis-associated cancer (AOM/DSS. B cell follicle formation increases in the context of the chronic inflammation associated to intestinal neoplasia, in this model. A network of lymphatic and haematic vessels surrounding B cell follicles is present and includes high endothelial venules (HEV. Future task is to determine whether lymphoid tissue contributes to the persistence of the tumor-associated inflammatory reaction, rather than represent a functional immune compartment, potentially participating to the anti tumor response.

  16. Alterations in body weight and biochemistry in patient treated with different psychotropic drugs in a clinic in Istanbul

    Directory of Open Access Journals (Sweden)

    Yeltekin Demirel,

    2009-08-01

    Full Text Available Aim Was to compare adult female patients receiving psychiatricdrugs with obese adult females who didn’t receive any drug treatmentwith respect to the alterations in body weight and biochemistry,and find out the contrubution of a team approach for the managementof these alterations.Methods A total of 102 female patients aged mean 40.9±12.4years who had been followed up and treated in the Psychiatry OutpatientClinics in Istanbul University for their psychiatric disordersand were complaining about increased body weight in thetreatment period were included. The controls were composed of261 females aged mean 39.8±13.0 years who had been referred byvarious departments to dietitians due to exogenous obesity but hadno endocrine-metabolic or psychiatric disorders or history of druguse. Initially, antropometric measurements and biochemical testswere performed for all patients.Results In the group receiving psychiatric treatment, the meanbody weight, BMI, waist and hip circumferences, body fat percentage(p<0.001; blood insulin, triglyceride, TSH, fibrinogenand homocysteine levels, and HOMA-IR were found to be higherthan those of the controls (p<0.05, whereas the total protein, albumin,zinc and folate levels were significantly lower (p<0.001.Conclusion The results of this study showed that patients whoneed psychopharmacotherapies were also more susceptible to severalmetabolic and cardiovascular disorders. Therefore, it wouldbe useful if psychiatric patients are treated with a multidisciplinaryteam approach consisting of an endocrinologist, psychiatrist and adietitian specialized in this area to prevent or delay the metabolicdisorders caused by psychiatric disorders and treatments.

  17. Nanoparticle Based Drug Delivery System: Milestone for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Gousia Chashoo

    2012-09-01

    Full Text Available The challenge of modern drug therapy is the optimization of the pharmacological action of the drugs coupled with the reduction of their toxic effects in vivo. The prime objectives in the design of drug delivery systems (DDS are the controlled delivery of the drug to its site of action at a therapeutically optimal rate and dosage to avoid toxicity and improve the drug effectiveness and therapeutic index. DDS has improved many of the pharmacological properties of conventional ("free" drugs including particulate carriers which are primarily composed of lipids and/or polymers and their associated therapeutics. It alters the pharmacokinetics (PK and biodistribution (BD of the associated drugs or functions as drug reservoir or both. Nanoparticles provide a range of new opportunities to increase the targeting of currently approved diagnostic and therapeutic agents to cancers. Nanoparticles carrying a chemotherapeutic can reduce the undesirable distribution of such agents. The problems related to cancer chemotherapy can partially be overcome by direct intratumoral delivery of controlled release biodegradable nanoparticles (NPs.

  18. Regression of subcutaneous B16 melanoma tumors after intratumoral delivery of an IL-15-expressing plasmid followed by in vivo electroporation

    OpenAIRE

    Ugen, KE; Kutzler, MA; Marrero, B; Westover, J; Coppola, D; Weiner, DB; Heller, R.

    2006-01-01

    In vivo electroporation has been used to efficiently deliver drugs and ‘therapeutic’ genes to tumors, including melanoma lesions. This study reports on the effect of intratumoral delivery of an optimized DNA plasmid expressing interleukin-15 (pIL-15) on established murine melanoma tumors. IL-15 has been demonstrated to have a pivotal role in the function of memory CD8+ T cells and natural killer cells, which are critical for tumor immunosurveillance. In this study, C57BL/6 mice were injected ...

  19. The Alterations in the Expression and Function of P-Glycoprotein in Vitamin A-Deficient Rats as well as the Effect of Drug Disposition in Vivo

    Directory of Open Access Journals (Sweden)

    Yubang Wang

    2015-12-01

    Full Text Available This study was aimed to investigate whether vitamin A deficiency could alter P-GP expression and function in tissues of rats and whether such effects affected the drug distribution in vivo of vitamin A-deficient rats. We induced vitamin A-deficient rats by giving them a vitamin A-free diet for 12 weeks. Then, Abcb1/P-GP expression was evaluated by qRT-PCR and Western blot. qRT-PCR analysis revealed that Abcb1a mRNA levels were increased in hippocampus and liver. In kidney, it only showed an upward trend. Abcb1b mRNA levels were increased in hippocampus, but decreased in cerebral cortex, liver and kidney. Western blot results were in good accordance with the alterations of Abcb1b mRNA levels. P-GP function was investigated through tissue distribution and body fluid excretion of rhodamine 123 (Rho123, and the results proclaimed that P-GP activities were also in good accordance with P-GP expression in cerebral cortex, liver and kidney. The change of drug distribution was also investigated through the tissue distribution of vincristine, and the results showed a significantly upward trend in all indicated tissues of vitamin A-deficient rats. In conclusion, vitamin A deficiency may alter Abcb1/P-GP expression and function in rat tissues, and the alterations may increase drug activity/toxicity through the increase of tissue accumulation.

  20. The Alterations in the Expression and Function of P-Glycoprotein in Vitamin A-Deficient Rats as well as the Effect of Drug Disposition in Vivo.

    Science.gov (United States)

    Wang, Yubang; Qin, Heng; Zhang, Chengxiang; Huan, Fei; Yan, Ting; Zhang, Lulu

    2015-12-29

    This study was aimed to investigate whether vitamin A deficiency could alter P-GP expression and function in tissues of rats and whether such effects affected the drug distribution in vivo of vitamin A-deficient rats. We induced vitamin A-deficient rats by giving them a vitamin A-free diet for 12 weeks. Then, Abcb1/P-GP expression was evaluated by qRT-PCR and Western blot. qRT-PCR analysis revealed that Abcb1a mRNA levels were increased in hippocampus and liver. In kidney, it only showed an upward trend. Abcb1b mRNA levels were increased in hippocampus, but decreased in cerebral cortex, liver and kidney. Western blot results were in good accordance with the alterations of Abcb1b mRNA levels. P-GP function was investigated through tissue distribution and body fluid excretion of rhodamine 123 (Rho123), and the results proclaimed that P-GP activities were also in good accordance with P-GP expression in cerebral cortex, liver and kidney. The change of drug distribution was also investigated through the tissue distribution of vincristine, and the results showed a significantly upward trend in all indicated tissues of vitamin A-deficient rats. In conclusion, vitamin A deficiency may alter Abcb1/P-GP expression and function in rat tissues, and the alterations may increase drug activity/toxicity through the increase of tissue accumulation.

  1. Behavioral and molecular neuroepigenetic alterations in prenatally stressed mice: relevance for the study of chromatin remodeling properties of antipsychotic drugs.

    Science.gov (United States)

    Dong, E; Tueting, P; Matrisciano, F; Grayson, D R; Guidotti, A

    2016-01-01

    We have recently reported that mice born from dams stressed during pregnancy (PRS mice), in adulthood, have behavioral deficits reminiscent of behaviors observed in schizophrenia (SZ) and bipolar (BP) disorder patients. Furthermore, we have shown that the frontal cortex (FC) and hippocampus of adult PRS mice, like that of postmortem chronic SZ patients, are characterized by increases in DNA-methyltransferase 1 (DNMT1), ten-eleven methylcytosine dioxygenase 1 (TET1) and exhibit an enrichment of 5-methylcytosine (5MC) and 5-hydroxymethylcytosine (5HMC) at neocortical GABAergic and glutamatergic gene promoters. Here, we show that the behavioral deficits and the increased 5MC and 5HMC at glutamic acid decarboxylase 67 (Gad1), reelin (Reln) and brain-derived neurotrophic factor (Bdnf) promoters and the reduced expression of the messenger RNAs (mRNAs) and proteins corresponding to these genes in FC of adult PRS mice is reversed by treatment with clozapine (5 mg kg(-1) twice a day for 5 days) but not by haloperidol (1 mg kg(-1) twice a day for 5 days). Interestingly, clozapine had no effect on either the behavior, promoter methylation or the expression of these mRNAs and proteins when administered to offspring of nonstressed pregnant mice. Clozapine, but not haloperidol, reduced the elevated levels of DNMT1 and TET1, as well as the elevated levels of DNMT1 binding to Gad1, Reln and Bdnf promoters in PRS mice suggesting that clozapine, unlike haloperidol, may limit DNA methylation by interfering with DNA methylation dynamics. We conclude that the PRS mouse model may be useful preclinically in screening for the potential efficacy of antipsychotic drugs acting on altered epigenetic mechanisms. Furthermore, PRS mice may be invaluable for understanding the etiopathogenesis of SZ and BP disorder and for predicting treatment responses at early stages of the illness allowing for early detection and remedial intervention. PMID:26756904

  2. Behavioral and molecular neuroepigenetic alterations in prenatally stressed mice: relevance for the study of chromatin remodeling properties of antipsychotic drugs

    Science.gov (United States)

    Dong, E; Tueting, P; Matrisciano, F; Grayson, D R; Guidotti, A

    2016-01-01

    We have recently reported that mice born from dams stressed during pregnancy (PRS mice), in adulthood, have behavioral deficits reminiscent of behaviors observed in schizophrenia (SZ) and bipolar (BP) disorder patients. Furthermore, we have shown that the frontal cortex (FC) and hippocampus of adult PRS mice, like that of postmortem chronic SZ patients, are characterized by increases in DNA-methyltransferase 1 (DNMT1), ten-eleven methylcytosine dioxygenase 1 (TET1) and exhibit an enrichment of 5-methylcytosine (5MC) and 5-hydroxymethylcytosine (5HMC) at neocortical GABAergic and glutamatergic gene promoters. Here, we show that the behavioral deficits and the increased 5MC and 5HMC at glutamic acid decarboxylase 67 (Gad1), reelin (Reln) and brain-derived neurotrophic factor (Bdnf) promoters and the reduced expression of the messenger RNAs (mRNAs) and proteins corresponding to these genes in FC of adult PRS mice is reversed by treatment with clozapine (5 mg kg−1 twice a day for 5 days) but not by haloperidol (1 mg kg−1 twice a day for 5 days). Interestingly, clozapine had no effect on either the behavior, promoter methylation or the expression of these mRNAs and proteins when administered to offspring of nonstressed pregnant mice. Clozapine, but not haloperidol, reduced the elevated levels of DNMT1 and TET1, as well as the elevated levels of DNMT1 binding to Gad1, Reln and Bdnf promoters in PRS mice suggesting that clozapine, unlike haloperidol, may limit DNA methylation by interfering with DNA methylation dynamics. We conclude that the PRS mouse model may be useful preclinically in screening for the potential efficacy of antipsychotic drugs acting on altered epigenetic mechanisms. Furthermore, PRS mice may be invaluable for understanding the etiopathogenesis of SZ and BP disorder and for predicting treatment responses at early stages of the illness allowing for early detection and remedial intervention. PMID:26756904

  3. Randomised, controlled study of intratumoral recombinant gamma-interferon treatment in newly diagnosed glioblastoma.

    OpenAIRE

    Färkkilä, M; Jääskeläinen, J.; Kallio, M. (Miki); Blomstedt, G.; Raininko, R; Virkkunen, P.; Paetau, A.; Sarelin, H.; Mäntylä, M

    1994-01-01

    The effect of intratumoral recombinant interferon gamma (rIFN-gamma) as adjuvant to open cytoreduction and external irradiation of 60 Gy on survival in adults with a newly diagnosed high-grade cerebral glioma was studied. The patients were randomised during surgery into the rIFN-gamma group (n = 14) or the control group (n = 17), and the latter received a subcutaneous reservoir of rIFN-gamma injections. Intratumoral rIFN-gamma was given three times a week for 4 weeks until radiotherapy, escal...

  4. ALTERED MRP IS ASSOCIATED WITH MULTIDRUG-RESISTANCE AND REDUCED DRUG ACCUMULATION IN HUMAN SW-1573 CELLS

    NARCIS (Netherlands)

    EIJDEMS, EWHM; ZAMAN, GJR; DEHAAS, M; VERSANTVOORT, CHM; FLENS, MJ; SCHEPER, RJ; KAMST, E; BORST, P; BAAS, F

    1995-01-01

    We have analysed the contribution of several parameters, e.g. drug accumulation, MDR1 P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and topoisomerase (topo) II, to drug resistance in a large set of drug-resistant variants of the human non-small-cell lung cancer cell line SW-15

  5. Interrogation of individual intratumoral B lymphocytes from lung cancer patients for molecular target discovery.

    Science.gov (United States)

    Campa, Michael J; Moody, M Anthony; Zhang, Ruijun; Liao, Hua-Xin; Gottlin, Elizabeth B; Patz, Edward F

    2016-02-01

    Intratumoral B lymphocytes are an integral part of the lung tumor microenvironment. Interrogation of the antibodies they express may improve our understanding of the host response to cancer and could be useful in elucidating novel molecular targets. We used two strategies to explore the repertoire of intratumoral B cell antibodies. First, we cloned VH and VL genes from single intratumoral B lymphocytes isolated from one lung tumor, expressed the genes as recombinant mAbs, and used the mAbs to identify the cognate tumor antigens. The Igs derived from intratumoral B cells demonstrated class switching, with a mean VH mutation frequency of 4%. Although there was no evidence for clonal expansion, these data are consistent with antigen-driven somatic hypermutation. Individual recombinant antibodies were polyreactive, although one clone demonstrated preferential immunoreactivity with tropomyosin 4 (TPM4). We found that higher levels of TPM4 antibodies were more common in cancer patients, but measurement of TPM4 antibody levels was not a sensitive test for detecting cancer. Second, in an effort to focus our recombinant antibody expression efforts on those B cells that displayed evidence of clonal expansion driven by antigen stimulation, we performed deep sequencing of the Ig genes of B cells collected from seven different tumors. Deep sequencing demonstrated somatic hypermutation but no dominant clones. These strategies may be useful for the study of B cell antibody expression, although identification of a dominant clone and unique therapeutic targets may require extensive investigation. PMID:26739486

  6. Intratumoral gas formation of HCC after trancatheter arterial chemoembolization(TACE)

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jou Yeoun; Park, Byeong Ho; Nam, Kyung Jin; Auh, Jong Young; Lee, Yung Il [College of Medicine Dong-A University, Pusan (Korea, Republic of); Koo, Bong Sig [Bong Saeng Memorial Hospital, Pusan (Korea, Republic of)

    1995-06-15

    To determine the factors predisposing to the intratumoral gas formation after TACE in the treatment of HCC. A total of 176 pathologically or clinically proven patients with HCC on whom CT scan had been performed in 2 weeks to 3 months after TACE were reviewed. The patients were classified in two groups; intratumoral gas-forming group(n = 18) and non-gas forming group(n = 158). Chi-square (X{sup 2}) test was applied to analyze the factors influencing to gas formation. The radiological factors studied were the morphologic type and location of HCC, presence or absence of tumor capsule on CT, the degree of tumor vascularities, presence of absence of portal vein thrombosis, presence or absence of arterioportal shunt, and TACE catheterization method on angiographic examination and the duration of post-TAE fever. Intratumoral gas formation after TACE occurred significantly in tumors with peripheral location or capsule on CT tumors with less vascularity or peripheral arterioportal shunt on angiographic examination, and TACE with selective catheterization method({rho} < 0.05). But the morphologic types of HCC and presence of main portal vein thrombosis were not significantly different between the two groups({rho} > 0.05). The average duration of fever sustained after TACE was longer in gas-forming group than those in non-gas forming group ({rho} < 0.05). TACE of HCC with weak collaterals or with peripherd prevent recanalization from collaterals has tendency to intratumoral gas from-his and prolonged fever duration.

  7. Intratumoral hemorrhage, vessel density, and the inflammatory reaction contribute to volume increase of sporadic vestibular schwannomas

    OpenAIRE

    de Vries, Maurits; Hogendoorn, Pancras C W; Briaire-de Bruyn, Inge; Malessy, Martijn J. A.; van der Mey, Andel G L

    2012-01-01

    Vestibular schwannomas show a large variation in growth rate, making prediction and anticipation of tumor growth difficult. More accurate prediction of clinical behavior requires better understanding of tumor biological factors influencing tumor progression. Biological processes like intratumoral hemorrhage, cell proliferation, microvessel density, and inflammation were analyzed in order to determine their role in vestibular schwannoma development. Tumor specimens of 67 patients surgically tr...

  8. Effect of intratumoral administration on biodistribution of 64Cu-labeled nanoshells

    Directory of Open Access Journals (Sweden)

    Xie H

    2012-05-01

    Full Text Available Huan Xie1, Beth Goins2, Ande Bao2, Zheng Jim Wang3, William T Phillips21Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, 2Department of Radiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 3MPI Research Inc, Mattawan, MIBackground: Gold nanoshells are excellent agents for photothermal ablation cancer therapy and are currently under clinical trial for solid tumors. Previous studies showed that passive delivery of gold nanoshells through intravenous administration resulted in limited tumor accumulation, which represents a major challenge for this therapy. In this report, the impact of direct intratumoral administration on the pharmacokinetics and biodistribution of the nanoshells was systematically investigated.Methods: The gold nanoshells were labeled with the radionuclide, copper-64 (64Cu. Intratumoral infusion of 64Cu-nanoshells and two controls, ie, 64Cu-DOTA (1,4,7,10-tetraazaciclododecane-1,4,7,10-tetraacetic acid and 64Cu-DOTA-PEG (polyethylene glycol, as well as intravenous injection of 64Cu-nanoshells were performed in nude rats, each with a head and neck squamous cell carcinoma xenograft. The pharmacokinetics was determined by radioactive counting of serial blood samples collected from the rats at different time points post-injection. Using positron emission tomography/computed tomography imaging, the in vivo distribution of 64Cu-nanoshells and the controls was monitored at various time points after injection. Organ biodistribution in the rats at 46 hours was analyzed by radioactive counting and compared between the different groups.Results: The resulting pharmacokinetic curves indicated a similar trend between the intratumorally injected agents, but a significant difference with the intravenously injected 64Cu-nanoshells. Positron emission tomography images and organ biodistribution results on rats after intratumoral administration

  9. Intravenous pretreatment with empty pH gradient liposomes alters the pharmacokinetics and toxicity of doxorubicin through in vivo active drug encapsulation.

    Science.gov (United States)

    Mayer, L D; Reamer, J; Bally, M B

    1999-01-01

    Liposomes have been used widely to improve the therapeutic activity of pharmaceutical agents. The traditional approach for such applications has been to formulate the pharmaceutical agent in liposomes prior to administration in vivo. In this report we demonstrate that liposomes exhibiting a transmembrane pH gradient injected intravenously (iv) can actively encapsulate doxorubicin in the circulation after iv administration of free drug. Small (110 nm) liposomes composed of phosphatidylcholine (PC)/cholesterol (Chol, 55:45 mol:mol) exhibiting a pH gradient (inside acidic) were administered iv 1 h prior to free doxorubicin, and plasma drug levels as well as toxicity and efficacy were evaluated. Predosing with egg PC/Chol pH gradient liposomes increased the plasma concentration of doxorubicin as much as 200-fold compared to free drug alone as well as to predosing with dipalmitoyl PC/Chol pH gradient liposomes or EPC/Chol liposomes without a pH gradient. The ability of the liposomes to alter the pharmacokinetics of doxorubicin was dependent on the presence of a transmembrane pH gradient and correlated with the extent of doxorubicin uptake into the liposomes at 37 degreesC in pH 7.5 buffer, indicating that doxorubicin was being actively accumulated in the circulating liposomes. This in vivo drug loading was achieved over a range of doxorubicin doses (5 mg/kg-40 mg/kg) and was dependent on the dose of EPC/Chol liposomes administered prior to free doxorubicin injection. The altered pharmacokinetic properties of doxorubicin associated with in vivo doxorubicin encapsulation were accompanied by a decrease in drug toxicity and maintained antitumor potency. These results suggest that pretreatment with empty liposomes exhibiting a pH gradient may provide a versatile and straightforward method for enhancing the pharmacological properties of many drugs that can accumulate into such vesicle systems at physiological temperatures.

  10. Pharmacological and genetic interventions in serotonin (5-HT)(2C) receptors to alter drug abuse and dependence processes

    NARCIS (Netherlands)

    Filip, Malgorzata; Spampinato, Umberto; McCreary, Andrew C.; Przegalinski, Edmund

    2012-01-01

    The present review provides an overview on serotonin (5-hydroxytryptamine; 5-HT)(2C) receptors and their relationship to drug dependence. We have focused our discussion on the impact of 5-HT2C receptors on the effects of different classes of addictive drugs, illustrated by reference to data using ph

  11. Disruption of BSEP Function in HepaRG Cells Alters Bile Acid Disposition and Is a Susceptive Factor to Drug-Induced Cholestatic Injury.

    Science.gov (United States)

    Qiu, Xi; Zhang, Yueping; Liu, Tongtong; Shen, Hong; Xiao, Yongling; Bourner, Maureen J; Pratt, Jennifer R; Thompson, David C; Marathe, Punit; Humphreys, W Griffith; Lai, Yurong

    2016-04-01

    In the present study, we characterized in vitro biosynthesis and disposition of bile acids (BAs) as well as hepatic transporter expression followed by ABCB11 (BSEP) gene knockout in HepaRG cells (HepaRG-KO cells). BSEP KO in HepaRG cells led to time-dependent BA accumulation, resulting in reduced biosynthesis of BAs and altered BA disposition. In HepaRG-KO cells, the expression of NTCP, OATP1B1, OATP2B1, BCRP, P-gp, and MRP2 were reduced, whereas MRP3 and OCT1 were up-regulated. As a result, BSEP KO altered the disposition of BAs and subsequently underwent adaptive regulations of BA synthesis and homeostasis to enable healthy growth of the cells. Although BSEP inhibitors caused no or slight increase of BAs in HepaRG wild type cells (HepaRG-WT cells), excessive intracellular accumulation of BAs was observed in HepaRG-KO cells exposed to bosentan and troglitazone, but not dipyridamole. LDH release in the medium was remarkably increased in HepaRG-KO cultures exposed to troglitazone (50 μM), suggesting drug-induced cellular injury. The results revealed that functional impairment of BSEP predisposes the cells to altered BA disposition and is a susceptive factor to drug-induced cholestatic injury. In total, BSEP inhibition might trigger the processes but is not a sole determinant of cholestatic cellular injury. As intracellular BA accumulation is determined by BSEP function and the subsequent adaptive gene regulation, assessment of intracellular BA accumulation in HepaRG-KO cells could be a useful approach to evaluate drug-induced liver injury (DILI) potentials of drugs that could disrupt other BA homeostasis pathways beyond BSEP inhibition. PMID:26910619

  12. GBR 12909 administration as an animal model of bipolar mania: time course of behavioral, brain oxidative alterations and effect of mood stabilizing drugs.

    Science.gov (United States)

    Queiroz, Ana Isabelle G; de Araújo, Maíra Moraes; da Silva Araújo, Tatiane; de Souza, Greicy Coelho; Cavalcante, Lígia Menezes; de Jesus Souza Machado, Michel; de Lucena, David Freitas; Quevedo, João; Macêdo, Danielle

    2015-10-01

    Polymorphisms in the human dopamine transporter (DAT) are associated with bipolar endophenotype. Based on this, the acute inhibition of DAT using GBR12909 causes behavioral alterations that are prevented by valproate (VAL), being related to a mania-like model. Herein our first aim was to analyze behavioral and brain oxidative alterations during a 24 h period post-GBR12909 to better characterize this model. Our second aim was to determine the preventive effects of lithium (Li) or VAL 2 h post-GBR12909. For this, adult male mice received GBR12909 or saline being evaluated at 2, 4, 8, 12 or 24 h post-administration. Hyperlocomotion, levels of reduced glutathione (GSH) and lipid peroxidation in brain areas were assessed at all these time-points. GBR12909 caused hyperlocomotion at 2 and 24 h. Rearing behavior increased only at 2 h. GSH levels decreased in the hippocampus and striatum at the time points of 2, 4, 8 and 12 h. Increased lipid peroxidation was detected at the time-points of 2 and 12 h in all brain areas studied. At the time-point of 2 h post-GBR12909 Li prevented the hyperlocomotion and rearing alterations, while VAL prevented only rearing alterations. Both drugs prevented pro-oxidative changes. In conclusion, we observed that the main behavioral and oxidative alterations took place at the time-period of 2 h post-GBR12909, what points to this time-period as the best for the assessment of alterations in this model. Furthermore, the present study expands the predictive validity of the model by the determination of the preventive effects of Li. PMID:26073232

  13. Radiotherapy of human sarcoma promotes an intratumoral immune effector signature

    OpenAIRE

    Sharma, Anu; Bode, Beata; Moch, Holger; Okoniewski, Michal; Knuth, Alexander; von Boehmer, Lotta; van den Broek, Maries

    2013-01-01

    PURPOSE: The tumor immune microenvironment plays a crucial role in the development and progression of cancer. Sarcomas are a group of heterogeneous soft tissue malignancies that are often treated with radiotherapy as a part of the treatment concept. There is increasing evidence that radiotherapy leads to alterations in the tumor microenvironment, particularly with respect to the immune infiltrate. The present study has been carried out to develop a better understanding of such changes followi...

  14. Prenatal stress alters progestogens to mediate susceptibility to sex-typical, stress-sensitive disorders, such as drug abuse: a review

    Directory of Open Access Journals (Sweden)

    Cheryl A Frye

    2011-10-01

    Full Text Available Maternal-offspring interactions begin prior to birth. Experiences of the mother during gestation play a powerful role in determining the developmental programming of the central nervous system. In particular, stress during gestation alters developmental programming of the offspring resulting in susceptibility to sex-typical and stress-sensitive neurodevelopmental, neuropsychiatric and neurodegenerative disorders. However, neither these effects, nor the underlying mechanisms, are well understood. Our hypothesis is that allopregnanolone, during gestation, plays a particularly vital role in mitigating effects of stress on the developing fetus and may mediate, in part, alterations apparent throughout the lifespan. Specifically, altered balance between glucocorticoids and progestogens during critical periods of development (stemming from psychological, immunological, and/or endocrinological stressors during gestation may permanently influence behavior, brain morphology, and/or neuroendocrine-sensitive processes. 5α-reduced progestogens are integral in the developmental programming of sex-typical, stress-sensitive, and/or disorder-relevant phenotypes. Prenatal stress may alter these responses and dysregulate allopregnanolone and its normative effects on stress axis function. As an example of a neurodevelopmental, neuropsychiatric and/or neurodegenerative process, this review focuses on responsiveness to drugs of abuse, which is sensitive to prenatal stress and progestogen milieu. This review explores the notion that allopregnanolone may effect, or be influenced by, prenatal stress, with consequences for neurodevelopmental-, neuropsychiatric- and/or neurodegenerative- relevant processes, such as addiction.

  15. Altered resting state functional connectivity of anterior cingulate cortex in drug naïve adolescents at the earliest stages of anorexia nervosa

    OpenAIRE

    Gaudio, Santino; Piervincenzi, Claudia; Beomonte Zobel, Bruno; Romana Montecchi, Francesca; Riva, Giuseppe; Carducci, Filippo; Cosimo Quattrocchi, Carlo

    2015-01-01

    Previous Resting-State Functional Connectivity (RSFC) studies have shown several functional alterations in adults with or recovered from long Anorexia Nervosa (AN). The aim of this paper was to investigate whole brain RSFC in adolescents with AN in the earliest stages, less than 6 months, of the disorder. Sixteen drug-naïve outpatient female adolescents with AN-restrictive type (AN-r) (mean age: 15,8; SD 1,7) were compared to 16 age-matched healthy female (mean age: 16,3; SD 1,4). Relevant re...

  16. Intratumoral regulatory T cells upregulate immunosuppressive molecules in head and neck cancer patients

    OpenAIRE

    Jie, H-B; Gildener-Leapman, N; Li, J.; Srivastava, R. M.; Gibson, S P; Whiteside, T L; Ferris, R. L.

    2013-01-01

    Background: Although regulatory T cells (Treg) are highly enriched in human tumours compared with peripheral blood, expression of the immune-checkpoint receptors, immunosuppressive molecules and function of Treg in these two sites remains undefined. Methods: Tumour-infiltrating lymphocytes and peripheral blood lymphocytes were isolated from a cohort of head and neck squamous cell carcinoma (HNSCC) patients. The immunosuppressive phenotypes and function of intratumoral Treg were compared with ...

  17. The role of intratumoral lymphovascular density in distinguishing primary from secondary mucinous ovarian tumors

    Directory of Open Access Journals (Sweden)

    Bernardo Gomes de Lacerda Almeida

    2014-12-01

    Full Text Available OBJECTIVE: Ovarian mucinous metastases commonly present as the first sign of the disease and are capable of simulating primary tumors. Our aim was to investigate the role of intratumoral lymphatic vascular density together with other surgical-pathological features in distinguishing primary from secondary mucinous ovarian tumors. METHODS: A total of 124 cases of mucinous tumors in the ovary (63 primary and 61 metastatic were compared according to their clinicopathological features and immunohistochemical profiles. The intratumoral lymphatic vascular density was quantified by counting the number of vessels stained by the D2-40 antibody. RESULTS: Metastases occurred in older patients and were associated with a higher proportion of tumors smaller than 10.0 cm; bilaterality; extensive necrosis; extraovarian extension; increased expression of cytokeratin 20, CDX2, CA19.9 and MUC2; and decreased expression of cytokeratin 7, CA125 and MUC5AC. The lymphatic vascular density was increased among primary tumors. However, after multivariate analysis, the best predictors of a secondary tumor were a size of 10.0 cm or less, bilaterality and cytokeratin 7 negativity. Lack of MUC2 expression was an important factor excluding metastasis. CONCLUSIONS: The higher intratumoral lymphatic vascular density in primary tumors when compared with secondary lesions suggests differences in the microenvironment. However, considering the differential diagnosis, the best discriminator of a secondary tumor is the combination of tumor size, laterality and the pattern of expression of cytokeratin 7 and MUC2.

  18. Improved Intratumoral Oxygenation Through Vascular Normalization Increases Glioma Sensitivity to Ionizing Radiation

    International Nuclear Information System (INIS)

    Purpose: Ionizing radiation, an important component of glioma therapy, is critically dependent on tumor oxygenation. However, gliomas are notable for areas of necrosis and hypoxia, which foster radioresistance. We hypothesized that pharmacologic manipulation of the typically dysfunctional tumor vasculature would improve intratumoral oxygenation and, thus, the antiglioma efficacy of ionizing radiation. Methods and Materials: Orthotopic U87 xenografts were treated with either continuous interferon-β (IFN-β) or bevacizumab, alone, or combined with cranial irradiation (RT). Tumor growth was assessed by quantitative bioluminescence imaging; the tumor vasculature using immunohistochemical staining, and tumor oxygenation using hypoxyprobe staining. Results: Both IFN-β and bevaziumab profoundly affected the tumor vasculature, albeit with different cellular phenotypes. IFN-β caused a doubling in the percentage of area of perivascular cell staining, and bevacizumab caused a rapid decrease in the percentage of area of endothelial cell staining. However, both agents increased intratumoral oxygenation, although with bevacizumab, the effect was transient, being lost by 5 days. Administration of IFN-β or bevacizumab before RT was significantly more effective than any of the three modalities as monotherapy or when RT was administered concomitantly with IFN-β or bevacizumab or 5 days after bevacizumab. Conclusion: Bevacizumab and continuous delivery of IFN-β each induced significant changes in glioma vascular physiology, improving intratumoral oxygenation and enhancing the antitumor activity of ionizing radiation. Additional investigation into the use and timing of these and other agents that modify the vascular phenotype, combined with RT, is warranted to optimize cytotoxic activity.

  19. The role of intratumoral lymphovascular density in distinguishing primary from secondary mucinous ovarian tumors

    Science.gov (United States)

    de Lacerda Almeida, Bernardo Gomes; Bacchi, Carlos E; Carvalho, Jesus P; Ferreira, Cristiane R; Carvalho, Filomena M

    2014-01-01

    OBJECTIVE: Ovarian mucinous metastases commonly present as the first sign of the disease and are capable of simulating primary tumors. Our aim was to investigate the role of intratumoral lymphatic vascular density together with other surgical-pathological features in distinguishing primary from secondary mucinous ovarian tumors. METHODS: A total of 124 cases of mucinous tumors in the ovary (63 primary and 61 metastatic) were compared according to their clinicopathological features and immunohistochemical profiles. The intratumoral lymphatic vascular density was quantified by counting the number of vessels stained by the D2-40 antibody. RESULTS: Metastases occurred in older patients and were associated with a higher proportion of tumors smaller than 10.0 cm; bilaterality; extensive necrosis; extraovarian extension; increased expression of cytokeratin 20, CDX2, CA19.9 and MUC2; and decreased expression of cytokeratin 7, CA125 and MUC5AC. The lymphatic vascular density was increased among primary tumors. However, after multivariate analysis, the best predictors of a secondary tumor were a size of 10.0 cm or less, bilaterality and cytokeratin 7 negativity. Lack of MUC2 expression was an important factor excluding metastasis. CONCLUSIONS: The higher intratumoral lymphatic vascular density in primary tumors when compared with secondary lesions suggests differences in the microenvironment. However, considering the differential diagnosis, the best discriminator of a secondary tumor is the combination of tumor size, laterality and the pattern of expression of cytokeratin 7 and MUC2. PMID:25518016

  20. Hydration and N-acetyl-l-cysteine alter the microstructure of human nail and bovine hoof: implications for drug delivery.

    Science.gov (United States)

    Nogueiras-Nieto, L; Gómez-Amoza, J L; Delgado-Charro, M B; Otero-Espinar, F J

    2011-12-20

    This work aimed to (a) characterize the microstructure and porosity of human nail and bovine hoof by mercury intrusion porosimetry and SEM image analysis, (b) study the effects of hydration and of N-acetyl-l-cysteine treatment on the microstructure of both membranes, and (c) determine whether the microstructural modifications were associated with changes in drug penetration measured by standard diffusion studies. Bovine hoof surface is more porous than nail surface although there were no differences between the mean surface pore sizes. Hydration and N-acetyl-l-cysteine increased the roughness and apparent surface porosity, and the porosity determined by mercury intrusion porosimetry of both membranes. Pore-Cor™ was used to generate tridimensional structures having percolation characteristics comparable to nail and hooves. The modeled structures were horizontally banded having an inner less-porous area which disappeared upon treatment. Treatment increased the predicted permeability of the simulated structures. Triamcinolone permeation increased significantly for hooves treated N-acetyl-l-cysteine, i.e., the membranes for which microstructural and permeability changes were the largest. Thus, microstructural changes determined via mercury intrusion porosimetry and subsequently modeled by Pore-Cor™ were related to drug diffusion. Further refinement of the technique will allow fast screening of penetration enhancers to be used in ungual drug delivery. PMID:21906642

  1. Hydration and N-acetyl-l-cysteine alter the microstructure of human nail and bovine hoof: implications for drug delivery.

    Science.gov (United States)

    Nogueiras-Nieto, L; Gómez-Amoza, J L; Delgado-Charro, M B; Otero-Espinar, F J

    2011-12-20

    This work aimed to (a) characterize the microstructure and porosity of human nail and bovine hoof by mercury intrusion porosimetry and SEM image analysis, (b) study the effects of hydration and of N-acetyl-l-cysteine treatment on the microstructure of both membranes, and (c) determine whether the microstructural modifications were associated with changes in drug penetration measured by standard diffusion studies. Bovine hoof surface is more porous than nail surface although there were no differences between the mean surface pore sizes. Hydration and N-acetyl-l-cysteine increased the roughness and apparent surface porosity, and the porosity determined by mercury intrusion porosimetry of both membranes. Pore-Cor™ was used to generate tridimensional structures having percolation characteristics comparable to nail and hooves. The modeled structures were horizontally banded having an inner less-porous area which disappeared upon treatment. Treatment increased the predicted permeability of the simulated structures. Triamcinolone permeation increased significantly for hooves treated N-acetyl-l-cysteine, i.e., the membranes for which microstructural and permeability changes were the largest. Thus, microstructural changes determined via mercury intrusion porosimetry and subsequently modeled by Pore-Cor™ were related to drug diffusion. Further refinement of the technique will allow fast screening of penetration enhancers to be used in ungual drug delivery.

  2. Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite's food vacuole and alter drug sensitivities.

    Science.gov (United States)

    Pulcini, Serena; Staines, Henry M; Lee, Andrew H; Shafik, Sarah H; Bouyer, Guillaume; Moore, Catherine M; Daley, Daniel A; Hoke, Matthew J; Altenhofen, Lindsey M; Painter, Heather J; Mu, Jianbing; Ferguson, David J P; Llinás, Manuel; Martin, Rowena E; Fidock, David A; Cooper, Roland A; Krishna, Sanjeev

    2015-01-01

    Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, are the major determinant of chloroquine resistance in this lethal human malaria parasite. Here, we describe P. falciparum lines subjected to selection by amantadine or blasticidin that carry PfCRT mutations (C101F or L272F), causing the development of enlarged food vacuoles. These parasites also have increased sensitivity to chloroquine and some other quinoline antimalarials, but exhibit no or minimal change in sensitivity to artemisinins, when compared with parental strains. A transgenic parasite line expressing the L272F variant of PfCRT confirmed this increased chloroquine sensitivity and enlarged food vacuole phenotype. Furthermore, the introduction of the C101F or L272F mutation into a chloroquine-resistant variant of PfCRT reduced the ability of this protein to transport chloroquine by approximately 93 and 82%, respectively, when expressed in Xenopus oocytes. These data provide, at least in part, a mechanistic explanation for the increased sensitivity of the mutant parasite lines to chloroquine. Taken together, these findings provide new insights into PfCRT function and PfCRT-mediated drug resistance, as well as the food vacuole, which is an important target of many antimalarial drugs.

  3. Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine and quinine in Guinea-Bissau between 2003 and 2012

    DEFF Research Database (Denmark)

    Jovel, Irina Tatiana; Kofoed, Poul-Erik; Rombo, Lars;

    2015-01-01

    BACKGROUND: Guinea-Bissau, West-Africa introduced artemether-lumefantrine in 2008 but quinine has also been commonly prescribed for treatment of uncomplicated Plasmodium falciparum malaria. An efficacious high-dose chloroquine treatment regimen was used previously. Temporal and seasonal changes...... of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine and quinine are described. METHODS: Pfcrt K76T, pfmdr1 gene copy numbers, N86Y, Y184F and 1034-1246 sequences were determined using PCR-based methods. Blood samples came from virtually all (n=1806) children aged.......001). CONCLUSIONS: Following the discontinuation of an effective chloroquine regimen highly artemether-lumefantrine susceptible P. falciparum (with pfcrt 76T) accumulated possibly due to suboptimal use of quinine and despite a fitness cost linked to 76T....

  4. Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine, and quinine in Guinea-Bissau between 2003 and 2012.

    Science.gov (United States)

    Jovel, Irina Tatiana; Kofoed, Poul-Erik; Rombo, Lars; Rodrigues, Amabelia; Ursing, Johan

    2015-02-01

    In 2008, artemether-lumefantrine was introduced in Guinea-Bissau, West Africa, but quinine has also been commonly prescribed for the treatment of uncomplicated Plasmodium falciparum malaria. An efficacious high-dose chloroquine treatment regimen was used previously. Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine, and quinine have been described. P. falciparum chloroquine resistance transporter (pfcrt) K76T, pfmdr1 gene copy numbers, pfmdr1 polymorphisms N86Y and Y184F, and pfmdr1 sequences 1034 to 1246 were determined using PCR-based methods. Blood samples came from virtually all (n=1,806) childrenquinine and despite a fitness cost linked to pfcrt 76T. (The studies reported here were registered at ClinicalTrials.gov under registration no. NCT00137514 [PSB-2001-chl-amo], NCT00137566 [PSB-2004-paracetamol], NCT00426439 [PSB-2006-coartem], NCT01157689 [AL-eff 2010], and NCT01704508 [Eurartesim 2012].).

  5. Deciphering intra-tumor heterogeneity of lung adenocarcinoma confirms that dominant, branching, and private gene mutations occur within individual tumor nodules.

    Science.gov (United States)

    Pelosi, Giuseppe; Pellegrinelli, Alessio; Fabbri, Alessandra; Tamborini, Elena; Perrone, Federica; Settanni, Giulio; Busico, Adele; Picciani, Benedetta; Testi, Maria Adele; Militti, Lucia; Maisonneuve, Patrick; Valeri, Barbara; Sonzogni, Angelica; Proto, Claudia; Garassino, Marina; De Braud, Filippo; Pastorino, Ugo

    2016-06-01

    While pulmonary adenocarcinoma (ADC) is morphologically heterogeneous, little is known about intra-tumor gene mutation heterogeneity (ITH). We therefore subjected 20 ADC nodules, 5 mutated for EGFR and 5 for KRAS, 5 with an ALK translocation, and 5 wild type (WT) for these alterations, to unsupervised next-generation sequencing of tumor regions from diverse architectural patterns. When 2 or more different gene mutations were found in a single tumor, this fulfilled the criteria for ITH. In the 84 studied tumor regions with diverse architecture, 71 gene mutations and 34 WT profiles were found. ITH was observed in 9/15 (60 %) ADC, 3 with an EGFR, 3 with a KRAS, and 3 with an ALK aberration, as reflected in 5, 6, and 9 additional mutations, respectively, detected in these tumors. EGFR mutations were observed in 21/22 and KRAS mutations in 18/22 tumor regions, suggesting that they appear early and have a driver role (dominant or trunk mutations). Branching mutations (in EZH2, PIK3CA, TP53, and EGFR exon 18) occurred in two or more regions, while private mutations (in ABL1, ALK, BRAF, HER2, KDR, LKB1, PTEN, MET, SMAD4, SMARCB1, and SRC) were confined to unique tumor samples of individual lesions, suggesting that they occurred later on during tumor progression. Patients with a tumor showing branching mutations ran a worse clinical course, independent of confounding factors. We conclude that in ADC, ITH exists in a pattern suggesting spatial and temporal hierarchy with dominant, branching, and private mutations. This is consistent with diverse intra-tumor clonal evolution, which has potential implications for patient prognosis or development of secondary therapy resistance. PMID:27056568

  6. Metabolic alterations and drug sensitivity of tyrosine kinase inhibitor resistant leukemia cells with a FLT3/ITD mutation.

    Science.gov (United States)

    Huang, Amin; Ju, Huai-Qiang; Liu, Kaiyan; Zhan, Guilian; Liu, Daolu; Wen, Shijun; Garcia-Manero, Guillermo; Huang, Peng; Hu, Yumin

    2016-07-28

    Internal tandem duplication (ITD) of the juxtamembrane region of FMS-like tyrosine kinase-3 (FLT3) receptor is a common type of mutation in adult acute myeloid leukemia (AML), and patient response to FLT3 inhibitors appears to be transient due to the emergence of drug resistance. We established two sorafenib-resistant cell lines carrying FLT3/ITD mutations, including the murine BaF3/ITD-R and human MV4-11-R cell lines. Gene expression profile analysis of the resistant and parental cells suggests that the highest ranked molecular and cellular functions of the differentially expressed genes are related to mitochondrial dysfunction. Both murine and human resistant cell lines display a longer doubling time, along with a significant inhibition of mitochondrial respiratory chain activity and substantial upregulation of glycolysis. The sorafenib-resistant cells exhibit increased expression of a majority of glycolytic enzymes, including hexokinase 2, which is also highly expressed in the mitochondrial fraction and is associated with resistance to apoptotic cell death. The sorafenib-resistant cells are collaterally sensitive to a number of glycolytic inhibitors including 2-deoxyglucose and 3-bromopyruvate propylester. Our study reveals a metabolic signature of sorafenib-resistant cells and suggests that glycolytic inhibition may override such resistance and warrant further clinical investigation. PMID:27132990

  7. Methamphetamine decreases CD4 T cell frequency and alters pro-inflammatory cytokine production in a model of drug abuse.

    Science.gov (United States)

    Mata, Mariana M; Napier, T Celeste; Graves, Steven M; Mahmood, Fareeha; Raeisi, Shohreh; Baum, Linda L

    2015-04-01

    The reason co-morbid methamphetamine use and HIV infection lead to more rapid progression to AIDS is unclear. We used a model of methamphetamine self-administration to measure the effect of methamphetamine on the systemic immune system to better understand the co-morbidity of methamphetamine and HIV. Catheters were implanted into the jugular veins of male, Sprague Dawley rats so they could self-administer methamphetamine (n=18) or be given saline (control; n=16) for 14 days. One day after the last operant session, blood and spleens were collected. We measured serum levels of pro-inflammatory cytokines, intracellular IFN-γ and TNF-α, and frequencies of CD4(+), CD8(+), CD200(+) and CD11b/c(+) lymphocytes in the spleen. Rats that self-administered methamphetamine had a lower frequency of CD4(+) T cells, but more of these cells produced IFN-γ. Methamphetamine did not alter the frequency of TNF-α-producing CD4(+) T cells. Methamphetamine using rats had a higher frequency of CD8(+) T cells, but fewer of them produced TNF-α. CD11b/c and CD200 expression were unchanged. Serum cytokine levels of IFN-γ, TNF-α and IL-6 in methamphetamine rats were unchanged. Methamphetamine lifetime dose inversely correlated with serum TNF-α levels. Our data suggest that methamphetamine abuse may exacerbate HIV disease progression by activating CD4 T cells, making them more susceptible to HIV infection, and contributing to their premature demise. Methamphetamine may also increase susceptibility to HIV infection, explaining why men who have sex with men (MSM) and frequently use methamphetamine are at the highest risk of HIV infection.

  8. Intratumoral administration of a recombinant canarypox virus expressing interleukin 12 in patients with metastatic melanoma.

    Science.gov (United States)

    Triozzi, Pierre L; Strong, Theresa V; Bucy, R Pat; Allen, Karen O; Carlisle, Ronda R; Moore, Susan E; Lobuglio, Albert F; Conry, Robert M

    2005-01-01

    The aim of this study was to evaluate the tolerability and activity of intratumoral administered human interleukin 12 encoded by a vector derived from the canarypox virus (ALVAC-IL-12). Nine patients with surgically incurable metastatic melanoma who had subcutaneous nodules available for injection were enrolled. ALVAC-IL-12 was administered by intratumoral injection on days 1, 4, 8, and 11. Tumor nodules greater than 2 cm in diameter were injected with 2 x 10(6) median tissue culture infectious doses (TCID(50)), and smaller tumors were injected with 1 x 10(6) TCID(50). The total dose per patient per time point ranged from 1 x 10(6) to 4 x 10(6) TCID(50). Toxicity was mild to moderate and consisted of inflammatory reactions at the injection site and fever associated with chills, myalgia, and fatigue. No dose-limiting toxicities occurred. Increases in IL-12 mRNA, and also increases in interferon gamma mRNA, were observed in ALVAC-IL-12-injected tumors compared with saline-injected control tumors in four of the nine patients. ALVAC-IL-12-injected tumors were also characterized by T cell infiltration. Three patients demonstrated increases in serum IL-12 and in interferon gamma levels. All patients developed neutralizing IgG antibody to the canarypox vector. One patient manifested a complete response of injected subcutaneous metastases and uninjected in-transit metastases. The intratumoral injection of ALVAC-IL-12 at these dose levels and according to this schedule was well tolerated and resulted in measurable biologic response in patients with metastatic melanoma. PMID:15703492

  9. Color Doppler ultrasound and gamma imaging of intratumorally injected 500 nm iron-silica nanoshells.

    Science.gov (United States)

    Liberman, Alexander; Wu, Zhe; Barback, Christopher V; Viveros, Robert; Blair, Sarah L; Ellies, Lesley G; Vera, David R; Mattrey, Robert F; Kummel, Andrew C; Trogler, William C

    2013-07-23

    Perfluoropentane gas filled iron-silica nanoshells have been developed as stationary ultrasound contrast agents for marking tumors to guide surgical resection. It is critical to establish their long-term imaging efficacy, as well as biodistribution. This work shows that 500 nm Fe-SiO2 nanoshells can be imaged by color Doppler ultrasound over the course of 10 days in Py8119 tumor bearing mice. The 500 nm nonbiodegradable SiO2 and biodegradable Fe-SiO2 nanoshells were functionalized with diethylenetriamine pentaacetic acid (DTPA) ligand and radiolabeled with (111)In(3+) for biodistribution studies in nu/nu mice. The majority of radioactivity was detected in the liver and kidneys following intravenous (IV) administration of nanoshells to healthy animals. By contrast, after nanoshells were injected intratumorally, most of the radioactivity remained at the injection site; however, some nanoshells escaped into circulation and were distributed similarly as those given intravenously. For intratumoral delivery of nanoshells and IV delivery to healthy animals, little difference was seen between the biodistribution of SiO2 and biodegradable Fe-SiO2 nanoshells. However, when nanoshells were administered IV to tumor bearing mice, a significant increase was observed in liver accumulation of SiO2 nanoshells relative to biodegradable Fe-SiO2 nanoshells. Both SiO2 and Fe-SiO2 nanoshells accumulate passively in proportion to tumor mass, during intravenous delivery of nanoshells. This is the first report of the biodistribution following intratumoral injection of any biodegradable silica particle, as well as the first report demonstrating the utility of DTPA-(111)In labeling for studying silica nanoparticle biodistributions.

  10. EGFR Regulates the Development and Microarchitecture of Intratumoral Angiogenic Vasculature Capable of Sustaining Cancer Cell Intravasation

    Directory of Open Access Journals (Sweden)

    Petra Minder

    2015-08-01

    Full Text Available Many malignant characteristics of cancer cells are regulated through pathways induced by the tyrosine kinase activity of the epidermal growth factor receptor (EGFR. Herein, we show that besides directly affecting the biology of cancer cells per se, EGFR also regulates the primary tumor microenvironment. Specifically, our findings demonstrate that both the expression and signaling activity of EGFR are required for the induction of a distinct intratumoral vasculature capable of sustaining tumor cell intravasation, a critical rate-limiting step in the metastatic cascade. An intravasation-sustaining mode of intratumoral angiogenic vessels depends on high levels of tumor cell EGFR and the interplay between EGFR-regulated production of interleukin 8 by tumor cells, interleukin-8–induced influx of tumor-infiltrating neutrophils delivering their unique matrix metalloproteinase-9, and neutrophil matrix metalloproteinase-9–dependent release of the vascular permeability and endothelial growth factor, VEGF. Our data indicate that through VEGF-mediated disruption of endothelial layer integrity and increase of intratumoral vasculature permeability, EGFR activity significantly facilitates active intravasation of cancer cells. Therefore, this study unraveled an important but overlooked function of EGFR in cancer, namely, its ability to create an intravasation-sustaining microenvironment within the developing primary tumor by orchestrating several interrelated processes required for the initial steps of cancer metastasis through vascular routes. Our findings also suggest that EGFR-targeted therapies might be more effective when implemented in cancer patients with early-staged primary tumors containing a VEGF-dependent angiogenic vasculature. Accordingly, early EGFR inhibition combined with various anti-VEGF approaches could synergistically suppress tumor cell intravasation through inhibiting the highly permeable angiogenic vasculature induced by EGFR

  11. Pan-cancer analysis of the extent and consequences of intratumor heterogeneity | Office of Cancer Genomics

    Science.gov (United States)

    Intratumor heterogeneity (ITH) drives neoplastic progression and therapeutic resistance. We used the bioinformatics tools 'expanding ploidy and allele frequency on nested subpopulations' (EXPANDS) and PyClone to detect clones that are present at a ≥10% frequency in 1,165 exome sequences from tumors in The Cancer Genome Atlas. 86% of tumors across 12 cancer types had at least two clones. ITH in the morphology of nuclei was associated with genetic ITH (Spearman's correlation coefficient, ρ = 0.24-0.41; P < 0.001).

  12. Imaging Intratumoral Nanoparticle Uptake After Combining Nanoembolization with Various Ablative Therapies in Hepatic VX2 Rabbit Tumors.

    Science.gov (United States)

    Tam, Alda L; Melancon, Marites P; Abdelsalam, Mohamed; Figueira, Tomas Appleton; Dixon, Katherine; McWatters, Amanda; Zhou, Min; Huang, Qian; Mawlawi, Osama; Dunner, Kenneth; Li, Chun; Gupta, Sanjay

    2016-02-01

    Combining image-guided therapy techniques for the treatment of liver cancers is a strategy that is being used to improve local tumor control rates. Here, we evaluate the intratumoral uptake of nanoparticles used in combination with radiofrequency ablation (RFA), irreversible electroporation (IRE), or laser induced thermal therapy (LITT). Eight rabbits with VX2 tumor in the liver underwent one of four treatments: (i) nanoembolization (NE) with radiolabeled, hollow gold nanoparticles loaded with doxorubicin (⁶⁴Cu-PEG-HAuNS-DOX); (ii) NE + RFA; (iii) NE + IRE; (iv) NE +LITT. Positron emission tomography/computed tomography (PET/CT) imaging was obtained 1-hr or 18-hrs after intervention. Tissue samples were collected for autoradiography and transmission electron microscopy (TEM) analysis. PET/CT imaging at 1-hr showed focal deposition of oil and nanoparticles in the tumor only after NE+ RFA but at 18-hrs, all animals had focal accumulation of oil and nanoparticles in the tumor region. Autoradiograph analysis demonstrated nanoparticle deposition in the tumor and in the ablated tissues adjacent to the tumor when NE was combined with ablation. TEM results showed the intracellular uptake of nanoparticles in tumor only after NE + IRE. Nanoparticles demonstrated a structural change, suggesting direct interaction, potentially leading to drug release, only after NE + LITT. The findings demonstrate that a combined NE and ablation treatment technique for liver tumors is feasible, resulting in deposition of nanoparticles in and around the tumor. Depending on the ablative energy applied, different effects are seen on nanoparticle localization and structure. These effects should be considered when designing nanoparticles for use in combination with ablation technologies. PMID:27305763

  13. Presence of intratumoral platelets is associated with tumor vessel structure and metastasis

    International Nuclear Information System (INIS)

    Platelets play a fundamental role in maintaining hemostasis and have been shown to participate in hematogenous dissemination of tumor cells. Abundant platelets were detected in the tumor microenvironment outside of the blood vessel, thus, platelet -tumor cell interaction outside of the bloodstream may play a role in regulating primary tumor growth and metastasis initiation. However, it is unclear that platelet depletion affects tumor vessel structure and dynamics. Using thrombocytopenia induction in two different tumor-bearing mouse models, tumor tissues were performed by Westernblotting and immunohistochemical staining. Vascular permeability was evaluated by determination of intratumoral Evans blue and Miles vascular permeability assay. Furthermore, microdialysis was used to examining the intratumoral extracellular angiogenic growth factors (VEGF, TGF-β) by ELISA. Platelet depletion showed no change in tumor growth and reduced lung metastasis. Platelet depletion led to reduced tumor hypoxia and Met receptor activation and was associated with a decreased release of MMP-2, 9, PAI-1, VEGF, and TGF-β. Tumor vessels in platelet-depleted mice showed impaired vessel density and maturation. Our findings demonstrate that platelets within the primary tumor microenvironment play a critical role in the induction of vascular permeability and initiation of tumor metastasis

  14. Ovarian fibromas: MR imaging findings with emphasis on intratumoral cyst formation

    International Nuclear Information System (INIS)

    Purpose: The purpose of this study was to assess MR imaging findings of ovarian fibromas with emphasis on intratumoral cyst formation. Materials and methods: MR images with a 1.5-T unit obtained in 17 consecutive patients (age range, 18–87 years; mean age, 58 years) with 17 histologically proven ovarian fibromas were retrospectively reviewed for the size, configuration, signal intensity of solid components, and presence of cystic degeneration and edema within tumor. Size, number, and location of intratumoral cysts were also assessed. Results: The maximum diameter of tumors ranged from 3.3 to 19.1 cm (mean, 10.9 cm). Seven (41%) tumors were multinodular. On T2-weighted images, solid components of tumors were heterogeneously mixed hypo- and hyperintensity in 16 (94%) tumors. Nine (53%) tumors demonstrated cysts and 16 (94%) demonstrated edema within tumor. The maximum diameter of the largest cysts ranged from 1.0 to 13.2 cm (mean, 6.4 cm), and the number of cysts per tumor ranged from 1 to 60 (mean, 15.6). Of the nine tumors with cystic formation, the predominant location of the cysts was peripheral in five (56%), exophytic in two (22%), central (11%) in one, and diffuse in one (11%). Conclusion: Peripheral or exophytic cyst formation may be characteristic MR imaging features with ovarian fibromas

  15. Expression and significance of intratumoral interleukin-12 and interleukin-18 in human gastric carcinoma

    Institute of Scientific and Technical Information of China (English)

    Zheng-Bao Ye; Tao Ma; Hao Li; Xiao-Long Jin; Hai-Min Xu

    2007-01-01

    AIM: To explore the effect of intratumoral expressions of interleukin-12 (IL-12) and interleukin-18 (IL-18) on clinical features, angiogenesis and prognosis of gastric carcinoma.METHODS: The expressions of IL-12 and IL-18 from 50 samples of gastric cancer tissue were analyzed by immunohistochemistry, and microvessel density (MVD) was determined with microscopic imaging analysis system.RESULTS: The positive expression rates of IL-12 and IL-18 were 44% (22/50) and 26% (13/50), respectively. IL-12 was significantly associated with pathologic differentiation, depth of invasion, lymph node metastasis, distant metastasis, and TNM stage, and IL-18 was closely related to distant metastasis. Intratumoral IL-12 and IL-18 expressions were not statistically related to MVD scoring. IL-12-positive patients survived significantly longer than those with IL-12-negative tumors, but there was no significant difference between IL-18-positive patients and IL-18-negative ones. The multivariate analysis with Cox proportional hazard model revealed IL-12, MVD and T stage were independent prognostic factors.CONCLUSION: The positive expressions of IL-12 and IL-18 can play an important role in progression and metastasis of gastric cancer, and IL-12 might be an independent factor of poor prognosis in gastric carcinoma.

  16. Ovarian fibromas: MR imaging findings with emphasis on intratumoral cyst formation

    Energy Technology Data Exchange (ETDEWEB)

    Kato, Hiroki, E-mail: hkato@gifu-u.ac.jp [Department of Radiology, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan); Kanematsu, Masayuki, E-mail: masa_gif@yahoo.co.jp [Department of Radiology, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan); High-level Imaging Diagnosis Center, Gifu University Hospital, 1-1 Yanagido, Gifu 501-1194 (Japan); Ono, Hiromi, E-mail: hiromi11_br@yahoo.co.jp [Department of Radiology, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan); Yano, Ryuichiro, E-mail: yanoryu@gifu-u.ac.jp [Department of Obstetrics and Gynecology, Gifu University School of Medicine, Gifu (Japan); Furui, Tatsuro, E-mail: furui@gifu-u.ac.jp [Department of Obstetrics and Gynecology, Gifu University School of Medicine, Gifu (Japan); Morishige, Ken-ichirou, E-mail: mken@gifu-u.ac.jp [Department of Obstetrics and Gynecology, Gifu University School of Medicine, Gifu (Japan); Hatano, Yuichiro, E-mail: yuha@gifu-u.ac.jp [Department of Pathology, Gifu University School of Medicine, Gifu (Japan)

    2013-09-15

    Purpose: The purpose of this study was to assess MR imaging findings of ovarian fibromas with emphasis on intratumoral cyst formation. Materials and methods: MR images with a 1.5-T unit obtained in 17 consecutive patients (age range, 18–87 years; mean age, 58 years) with 17 histologically proven ovarian fibromas were retrospectively reviewed for the size, configuration, signal intensity of solid components, and presence of cystic degeneration and edema within tumor. Size, number, and location of intratumoral cysts were also assessed. Results: The maximum diameter of tumors ranged from 3.3 to 19.1 cm (mean, 10.9 cm). Seven (41%) tumors were multinodular. On T2-weighted images, solid components of tumors were heterogeneously mixed hypo- and hyperintensity in 16 (94%) tumors. Nine (53%) tumors demonstrated cysts and 16 (94%) demonstrated edema within tumor. The maximum diameter of the largest cysts ranged from 1.0 to 13.2 cm (mean, 6.4 cm), and the number of cysts per tumor ranged from 1 to 60 (mean, 15.6). Of the nine tumors with cystic formation, the predominant location of the cysts was peripheral in five (56%), exophytic in two (22%), central (11%) in one, and diffuse in one (11%). Conclusion: Peripheral or exophytic cyst formation may be characteristic MR imaging features with ovarian fibromas.

  17. Naproxen, a Nonsteroidal Anti-Inflammatory Drug, Can Affect Daily Hypobaric Hypoxia-Induced Alterations of Monoamine Levels in Different Areas of the Brain in Male Rats.

    Science.gov (United States)

    Goswami, Ananda Raj; Dutta, Goutam; Ghosh, Tusharkanti

    2016-06-01

    Goswami, Ananda Raj, Goutam Dutta, and Tusharkanti Ghosh. Naproxen, a nonsteroidal anti-inflammatory drug can affect daily hypobaric hypoxia-induced alterations of monoamine levels in different areas of the brain in male rats. High Alt Med Biol. 17:133-140, 2016.-The oxidative stress (OS)-induced prostaglandin (PG) release, in hypobaric hypoxic (HHc) condition, may be linked with the changes of brain monoamines. The present study intends to explore the changes of monoamines in hypothalamus (H), cerebral cortex (CC), and cerebellum (CB) along with the motor activity in rats after exposing them to simulated hypobaric condition and the role of PGs on the daily hypobaric hypoxia (DHH)-induced alteration of brain monoamines by administering, an inhibitor of PG synthesis, naproxen. The rats were exposed to a decompression chamber at 18,000 ft for 8 hours per day for 6 days after administration of vehicle or naproxen (18 mg/kg body wt.). The monoamine levels (epinephrine, E; norepinephrine, NE; dopamine, DA; and 5-hydroxytryptamine, 5-HT) in CC, CB, and H were assayed by high-performance liquid chromatography (HPLC) with electrochemical detection, and the locomotor behavior was measured by open field test. The NE and DA levels were decreased in CC, CB, and H of the rat brain in HHc condition. The E and 5-HT levels were decreased in CC, but in H and CB, they remained unaltered in HHc condition. These DHH-induced changes of monoamines in brain areas were prevented after administration of naproxen in HHc condition. The locomotor behavior remained unaltered in HHc condition and after administration of naproxen in HHc condition. The DHH-induced changes of monoamines in the brain in HHc condition are probably linked with PGs that may be induced by OS. PMID:26894935

  18. Altered resting state functional connectivity of anterior cingulate cortex in drug naïve adolescents at the earliest stages of anorexia nervosa.

    Science.gov (United States)

    Gaudio, Santino; Piervincenzi, Claudia; Beomonte Zobel, Bruno; Romana Montecchi, Francesca; Riva, Giuseppe; Carducci, Filippo; Quattrocchi, Carlo Cosimo

    2015-01-01

    Previous Resting-State Functional Connectivity (RSFC) studies have shown several functional alterations in adults with or recovered from long Anorexia Nervosa (AN). The aim of this paper was to investigate whole brain RSFC in adolescents with AN in the earliest stages, less than 6 months, of the disorder. Sixteen drug-naïve outpatient female adolescents with AN-restrictive type (AN-r) (mean age: 15,8; SD 1,7) were compared to 16 age-matched healthy female (mean age: 16,3; SD 1,4). Relevant resting state networks (RSNs) were identified using independent component analysis (ICA) from functional magnetic resonance imaging data; a dual regression technique was used to detect between-group differences in the RSNs. Between-group differences of the functional connectivity maps were found in the executive control network (ECN). Particularly, decreased temporal correlation was observed in AN-r patients relative to healthy controls between the ECN functional connectivity maps and the anterior cingulate cortex (p emotional processing, our findings could explain the impaired cognitive flexibility in relation to body image and appetite in AN patients. PMID:26043139

  19. Altered resting state functional connectivity of anterior cingulate cortex in drug naïve adolescents at the earliest stages of anorexia nervosa

    Science.gov (United States)

    Gaudio, Santino; Piervincenzi, Claudia; Beomonte Zobel, Bruno; Romana Montecchi, Francesca; Riva, Giuseppe; Carducci, Filippo; Cosimo Quattrocchi, Carlo

    2015-01-01

    Previous Resting-State Functional Connectivity (RSFC) studies have shown several functional alterations in adults with or recovered from long Anorexia Nervosa (AN). The aim of this paper was to investigate whole brain RSFC in adolescents with AN in the earliest stages, less than 6 months, of the disorder. Sixteen drug-naïve outpatient female adolescents with AN-restrictive type (AN-r) (mean age: 15,8; SD 1,7) were compared to 16 age-matched healthy female (mean age: 16,3; SD 1,4). Relevant resting state networks (RSNs) were identified using independent component analysis (ICA) from functional magnetic resonance imaging data; a dual regression technique was used to detect between-group differences in the RSNs. Between-group differences of the functional connectivity maps were found in the executive control network (ECN). Particularly, decreased temporal correlation was observed in AN-r patients relative to healthy controls between the ECN functional connectivity maps and the anterior cingulate cortex (p < 0.05 corrected). Our results in AN adolescents may represent an early trait-related biomarker of the disease. Considering that the above mentioned network and its area are mainly involved in cognitive control and emotional processing, our findings could explain the impaired cognitive flexibility in relation to body image and appetite in AN patients. PMID:26043139

  20. Intratumoral macrophages contribute to epithelial-mesenchymal transition in solid tumors

    International Nuclear Information System (INIS)

    Several stromal cell subtypes including macrophages contribute to tumor progression by inducing epithelial-mesenchymal transition (EMT) at the invasive front, a mechanism also linked to metastasis. Tumor associated macrophages (TAM) reside mainly at the invasive front but they also infiltrate tumors and in this process they mainly assume a tumor promoting phenotype. In this study, we asked if TAMs also regulate EMT intratumorally. We found that TAMs through TGF-β signaling and activation of the β-catenin pathway can induce EMT in intratumoral cancer cells. We depleted macrophages in F9-teratocarcinoma bearing mice using clodronate-liposomes and analyzed the tumors for correlations between gene and protein expression of EMT-associated and macrophage markers. The functional relationship between TAMs and EMT was characterized in vitro in the murine F9 and mammary gland NMuMG cells, using a conditioned medium culture approach. The clinical relevance of our findings was evaluated on a tissue microarray cohort representing 491 patients with non-small cell lung cancer (NSCLC). Gene expression analysis of F9-teratocarcinomas revealed a positive correlation between TAM-densities and mesenchymal marker expression. Moreover, immunohistochemistry showed that TAMs cluster with EMT phenotype cells in the tumors. In vitro, long term exposure of F9-and NMuMG-cells to macrophage-conditioned medium led to decreased expression of the epithelial adhesion protein E-cadherin, activation of the EMT-mediating β-catenin pathway, increased expression of mesenchymal markers and an invasive phenotype. In a candidate based screen, macrophage-derived TGF-β was identified as the main inducer of this EMT-associated phenotype. Lastly, immunohistochemical analysis of NSCLC patient samples identified a positive correlation between intratumoral macrophage densities, EMT markers, intraepithelial TGF-β levels and tumor grade. Data presented here identify a novel role for macrophages in EMT

  1. Intratumoral macrophages contribute to epithelial-mesenchymal transition in solid tumors

    Directory of Open Access Journals (Sweden)

    Bonde Anne-Katrine

    2012-01-01

    Full Text Available Abstract Background Several stromal cell subtypes including macrophages contribute to tumor progression by inducing epithelial-mesenchymal transition (EMT at the invasive front, a mechanism also linked to metastasis. Tumor associated macrophages (TAM reside mainly at the invasive front but they also infiltrate tumors and in this process they mainly assume a tumor promoting phenotype. In this study, we asked if TAMs also regulate EMT intratumorally. We found that TAMs through TGF-β signaling and activation of the β-catenin pathway can induce EMT in intratumoral cancer cells. Methods We depleted macrophages in F9-teratocarcinoma bearing mice using clodronate-liposomes and analyzed the tumors for correlations between gene and protein expression of EMT-associated and macrophage markers. The functional relationship between TAMs and EMT was characterized in vitro in the murine F9 and mammary gland NMuMG cells, using a conditioned medium culture approach. The clinical relevance of our findings was evaluated on a tissue microarray cohort representing 491 patients with non-small cell lung cancer (NSCLC. Results Gene expression analysis of F9-teratocarcinomas revealed a positive correlation between TAM-densities and mesenchymal marker expression. Moreover, immunohistochemistry showed that TAMs cluster with EMT phenotype cells in the tumors. In vitro, long term exposure of F9-and NMuMG-cells to macrophage-conditioned medium led to decreased expression of the epithelial adhesion protein E-cadherin, activation of the EMT-mediating β-catenin pathway, increased expression of mesenchymal markers and an invasive phenotype. In a candidate based screen, macrophage-derived TGF-β was identified as the main inducer of this EMT-associated phenotype. Lastly, immunohistochemical analysis of NSCLC patient samples identified a positive correlation between intratumoral macrophage densities, EMT markers, intraepithelial TGF-β levels and tumor grade. Conclusions Data

  2. Gene transfer of somatostatin receptor type 2 by intratumoral injection inhibits established pancreatic carcinoma xenografts

    Institute of Scientific and Technical Information of China (English)

    Zhi-Yong Du; Ren-Yi Qin; Wei Xia; Rui Tian; Manoj Kumar

    2005-01-01

    AIM: To investigate the therapeutic effect of somatostatin receptor type 2 (SSTR2) gene transfection on pancreatic carcinoma xenograftsin vivo in experimental cancers.METHODS: Human pancreatic cancer cell line Panc-1 was inoculated subcutaneously into the back of nude mice. When tumor nodules were grown as large as about 5 mm×5 mm days after inoculation, the mice were randomly divided into 3 groups (6 mice in each group). Group Ⅰ served as untreated control group. Group Ⅱ received an intratumoral injection of a combination of human cytomegalovirus promoter-6C (pCMV-6C) and lipofectamine 2000. Group Ⅲ received an intratumoral injection of a combination of pCMV-6C-SSTR2 and lipofectamine 2000. The rate of tumor growth was compared among these three groups. The expression of SSTR2 in these tumors was detected by immunohistochemistry and Western-blot. Apoptosis index (AI) in these tumors was examined by using TUNEL in situ.RESULTS: Intratumoral injection of a combination of pCMV-6C-SSTR2 and lipofectamine 2000 resulted in the expression of SSTR2 protein. The tumor size and weight in group Ⅲ (0.318±0.098 cm3, and 0.523±0.090 g,respectively) were significantly lower than those in group Ⅰ (2.058±0.176 cm3, and 1.412±0.146 g, respectively) and group Ⅱ (2.025±0.163 cm3, and 1.365±0.116 g, respectively)(P<0.05) The AI in group Ⅲ (1.47±0.13%) was significantly higher than that in group Ⅰ (0.56±0.09%) and group Ⅱ (0.57±0.11%) (P<0.05). But there were no significant differences between groups Ⅰ and Ⅱ.CONCLUSION: Our data demonstrate that re-expression of SSTR2 gene has antitumor effects on experimental pancreatic cancer. Restoration of SSTR2 gene expression through gene transfer in vivo might be a potential gene therapy strategy for human pancreatic cancer.

  3. Drug Addiction

    OpenAIRE

    Justinova, Zuzana; Panlilio, Leigh V; Goldberg, Steven R.

    2009-01-01

    Many drugs of abuse, including cannabinoids, opioids, alcohol and nicotine, can alter the levels of endocannabinoids in the brain. Recent studies show that release of endocannabinoids in the ventral tegmental area can modulate the reward-related effects of dopamine and might therefore be an important neurobiological mechanism underlying drug addiction. There is strong evidence that the endocannabinoid system is involved in drug-seeking behavior (especially behavior that is reinforced by drug-...

  4. High intratumoral macrophage content is an adverse prognostic feature in anaplastic large cell lymphoma

    DEFF Research Database (Denmark)

    Pedersen, Martin B; Danielsen, Allan V; Hamilton-Dutoit, Stephen J;

    2014-01-01

    AIMS: Macrophage infiltration has been associated with prognosis in several cancers, including lymphoma, but has not been assessed systematically in anaplastic large cell lymphoma (ALCL). The aim of the study was to correlate expression of the macrophage-associated antigens CD68 and CD163 with pre......-therapeutic parameters and outcome in a cohort of treatment-naive ALCL patients. METHODS AND RESULTS: Pre-therapeutic tumour specimens from 52 patients with ALCL were included in a tissue microarray. The intratumoral macrophage content was assessed by immunohistochemical staining for CD68 and CD163, and quantified using......-free survival in ALK-negative patients (P macrophages correlates with an adverse outcome in ALK-negative ALCL....

  5. Intratumoral metabolic heterogeneity predicts invasive components in breast ductal carcinoma in situ

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Hai-Jeon [Ewha Womans University School of Medicine, Department of Nuclear Medicine, Yangchun-Ku, Seoul (Korea, Republic of); Kim, Yemi [Ewha Womans University, Clinical Research Institute, Seoul (Korea, Republic of); Kim, Bom Sahn [Ewha Womans University School of Medicine, Department of Nuclear Medicine, Yangchun-Ku, Seoul (Korea, Republic of); Ewha Womans University, Clinical Research Institute, Seoul (Korea, Republic of)

    2015-12-15

    This study investigated whether texture-based imaging parameters could identify invasive components of ductal carcinoma in situ (DCIS). We enrolled 65 biopsy-confirmed DCIS patients (62 unilateral, 3 bilateral) who underwent {sup 18}F-FDG PET, diffusion-weighted imaging (DWI), or breast-specific gamma imaging (BSGI). We measured SUV{sub max} and intratumoral metabolic heterogeneity by the area under the curve (AUC) of cumulative SUV histograms (CSH) on PET, tumour-to-normal ratio (TNR) and coefficient of variation (COV) as an index of heterogeneity on BSGI, minimum ADC (ADC{sub min}) and ADC difference (ADC{sub diff}) as an index of heterogeneity on DWI. After surgery, final pathology was categorized as pure-DCIS (DCIS-P), DCIS with microinvasion (DCIS-MI), or invasive ductal carcinoma (IDC). Clinicopathologic features of DCIS were correlated with final classification. Final pathology confirmed 44 DCIS-P, 14 DCIS-MI, and 10 IDC. The invasive component of DCIS was significantly correlated with higher SUV{sub max} (p = 0.017) and lower AUC-CSH (p < 0.001) on PET, higher TNR (p = 0.008) and COV (p = 0.035) on BSGI, lower ADC{sub min} (p = 0.016) and higher ADC{sub diff} (p = 0.009) on DWI, and larger pathologic size (p = 0.018). On multiple regression analysis, AUC-CSH was the only significant predictor of invasive components (p = 0.044). The intratumoral metabolic heterogeneity of {sup 18}F-FDG PET was the most important predictor of invasive components of DCIS. (orig.)

  6. Repeated exposure to amphetamine during adolescence alters inhibitory tone in the medial prefrontal cortex following drug re-exposure in adulthood.

    Science.gov (United States)

    Paul, Kush; Kang, Shuo; Cox, Charles L; Gulley, Joshua M

    2016-08-01

    Behavioral sensitization following repeated amphetamine (AMPH) exposure is associated with changes in GABA function in the medial prefrontal cortex (mPFC). In rats exposed to AMPH during adolescence compared to adulthood, there are unique patterns of sensitization that may reflect age-dependent differences in drug effects on prefrontal GABAergic function. In the current study, we used a sensitizing regimen of repeated AMPH exposure in adolescent and adult rats to determine if a post-withdrawal AMPH challenge would alter inhibitory transmission in the mPFC in a manner that depends on age of exposure. Male Sprague-Dawley rats were treated with saline or 3mg/kg AMPH (i.p.) during adolescence [postnatal day (P) 27-P45] or adulthood (P85- P103) and were sacrificed either at similar ages in adulthood (∼P133; experiment 1) or after similar withdrawal times (3-4 weeks; experiment 2). Spontaneous inhibitory postsynaptic currents (sIPSCs) were recorded in vitro from deep layer pyramidal cells in the mPFC using the whole-cell configuration. We found no effect of AMPH pre-exposure on baseline sIPSC frequency. Subsequent application of AMPH (25μM) produced a stable increase in sIPSC frequency in controls, suggesting that AMPH increases inhibitory tone in the mPFC. However, AMPH failed to increase sIPSCs in adolescent- or adult-exposed rats. In experiment 2, where withdrawal period was kept similar for both exposure groups, AMPH induced a suppression of sIPSC activity in adolescent-exposed rats. These results suggest that sensitizing treatment with AMPH during adolescence or adulthood dampens inhibitory influences on mPFC pyramidal cells, but potentially through different mechanisms. PMID:27085589

  7. Ruptured high flow gastric varices with an intratumoral arterioportal shunt treated with balloon-occluded retrograde transvenous obliteration during temporary balloon occlusion of a hepatic artery

    Institute of Scientific and Technical Information of China (English)

    Motoki Nakai; Morio Sato; Hirohiko Tanihata; Tetsuo Sonomura; Shinya Sahara; Nobuyuki Kawai; Masashi Kimura; Masaki Terada

    2006-01-01

    A patient presented with hematemesis due to gastric variceal bleeding with an intratumoral arterioportal shunt. Contrast-enhanced CT revealed gastric varices and hepatocellular carcinoma with tumor thrombi in the right portal vein. Angiography and angio-CT revealed a marked intratumoral arterioportal shunt accompanied with reflux into the main portal vein and gastric varices. Balloon-occluded retrograde venography from the gastro-renal shunt showed no visualization of gastric varices due to rapid blood flow through the intratumoral arterioportal shunt. The hepatic artery was temporarily occluded with a balloon catheter to reduce the blood flow through the arterioportal shunt, and then concurrent balloon-occluded retrograde transvenous obliteration (BRTO) was achieved. Vital signs stabilized immediately thereafter, and contrast-enhanced CT revealed thrombosed gastric varices. Worsening of hepatic function was not recognized. BRTO combined with temporary occlusion of the hepatic artery is a feasible interventional procedure for ruptured high flow gastric varices with an intratumoral arterioportal shunt.

  8. Combination therapy using intratumoral bacillus Calmette-Guerin (BCG) and vincristine in dogs with transmissible venereal tumours : therapeutic efficacy and histological changes : article

    OpenAIRE

    S. Mukaratirwa; S. Chitanga; T. Chimatira; C. Makuleke; S.T. Sayi; E. Bhebhe

    2009-01-01

    Therapeutic efficacy and histological changes after bacillus Calmette-Guerin (BCG), vincristine and BCG/vincristine combination therapy of canine transmissible venereal tumours (CTVT) were studied. Twenty dogs with naturally occurring CTVT in the progression stage were divided into 4 groups and treated with intratumoral BCG, vincristine, BCG/vincristine combination therapy or intratumoral buffered saline (control group). Tumour sizes were determined weekly and tumour response to therapy was a...

  9. Suppression of intratumoral CCL22 by type i interferon inhibits migration of regulatory T cells and blocks cancer progression.

    Science.gov (United States)

    Anz, David; Rapp, Moritz; Eiber, Stephan; Koelzer, Viktor H; Thaler, Raffael; Haubner, Sascha; Knott, Max; Nagel, Sarah; Golic, Michaela; Wiedemann, Gabriela M; Bauernfeind, Franz; Wurzenberger, Cornelia; Hornung, Veit; Scholz, Christoph; Mayr, Doris; Rothenfusser, Simon; Endres, Stefan; Bourquin, Carole

    2015-11-01

    The chemokine CCL22 is abundantly expressed in many types of cancer and is instrumental for intratumoral recruitment of regulatory T cells (Treg), an important subset of immunosuppressive and tumor-promoting lymphocytes. In this study, we offer evidence for a generalized strategy to blunt Treg activity that can limit immune escape and promote tumor rejection. Activation of innate immunity with Toll-like receptor (TLR) or RIG-I-like receptor (RLR) ligands prevented accumulation of Treg in tumors by blocking their immigration. Mechanistic investigations indicated that Treg blockade was a consequence of reduced intratumoral CCL22 levels caused by type I IFN. Notably, stable expression of CCL22 abrogated the antitumor effects of treatment with RLR or TLR ligands. Taken together, our findings argue that type I IFN blocks the Treg-attracting chemokine CCL22 and thus helps limit the recruitment of Treg to tumors, a finding with implications for cancer immunotherapy. PMID:26432403

  10. Intratumoral FoxP3 expression is associated with angiogenesis and prognosis in malignant canine mammary tumors.

    Science.gov (United States)

    Carvalho, Maria Isabel; Pires, Isabel; Prada, Justina; Gregório, Hugo; Lobo, Luis; Queiroga, Felisbina L

    2016-10-01

    The activity of regulatory T cells (Tregs) is closely associated with the expression of FoxP3 transcription factor. FoxP3 regulatory T cells (FoxP3Treg) have immunosuppressive properties and can work for prevention of harmful autoimmune responses, however can also interfere with beneficial anti-tumor immunity. In human breast cancer these cells play a crucial role in tumor progression. In canine mammary tumors (CMT) this topic is not well-documented. This study included 80 malignant CMT and studied, by immunohistochemistry, the intratumoral FoxP3 expression together with microvessel density (MVD), vascular endothelial growth factor (VEGF) and several clinicopathological characteristics. Abundant FoxP3Treg cells were associated with tumor necrosis (p=0.001), high mitotic grade (paggression in these tumors. The association of intratumoral FoxP3 expression with shorter OS in multivariate analysis suggests the usefulness of Treg cells as an independent prognostic marker. PMID:27496736

  11. Correlation of intra-tumor 18F-FDG uptake heterogeneity indices with perfusion CT derived parameters in colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Florent Tixier

    Full Text Available Thirty patients with proven colorectal cancer prospectively underwent integrated 18F-FDG PET/DCE-CT to assess the metabolic-flow phenotype. Both CT blood flow parametric maps and PET images were analyzed. Correlations between PET heterogeneity and perfusion CT were assessed by Spearman's rank correlation analysis.Blood flow visualization provided by DCE-CT images was significantly correlated with 18F-FDG PET metabolically active tumor volume as well as with uptake heterogeneity for patients with stage III/IV tumors (|ρ|:0.66 to 0.78; p-value<0.02.The positive correlation found with tumor blood flow indicates that intra-tumor heterogeneity of 18F-FDG PET accumulation reflects to some extent tracer distribution and consequently indicates that 18F-FDG PET intra-tumor heterogeneity may be associated with physiological processes such as tumor vascularization.

  12. Mechanisms of acquired resistance to androgen receptor targeting drugs in castration resistant prostate cancer

    OpenAIRE

    Chism, David D.; De Silva, Dinuka; Whang, Young E.

    2014-01-01

    After initial response to androgen receptor targeting drugs abiraterone or enzalutamide, most patients develop progressive disease and therefore, castration resistant prostate cancer (CRPC) remains a terminal disease. Multiple mechanisms underlying acquired resistance have been postulated. Intratumoral androgen synthesis may resume after abiraterone treatment. A point mutation in the ligand binding domain of androgen receptor may confer resistance to enzalutamide. Emergence of androgen recept...

  13. Histological evaluation of intratumoral myxoma virus treatment in an immunocompetent mouse model of melanoma

    Directory of Open Access Journals (Sweden)

    Doty RA

    2013-01-01

    Full Text Available Rosalinda A Doty,1 Jia Liu,2 Grant McFadden,2 Edward J Roy,3 Amy L MacNeill11Department of Pathobiology, University of Illinois, Urbana, IL, 2Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, 3Department of Molecular and Integrative Physiology, University of Illinois, Urbana, IL, USAAbstract: Two recombinant myxoma viruses (MYXV expressing a fluorescent protein [MYXV-Tred] and MYXV-Tred encoding murine interleukin-15 [MYXV-IL15] were evaluated for therapeutic effects in an aggressive B16F10 melanoma model in immunocompetent mice. It was hypothesized that continuous expression of IL-15 within a tumor would recruit cytotoxic effector cells to induce an antitumor immune response and improve treatment efficacy. Weekly intratumoral injections were given to evaluate the effect of treatment on the median survival time of C57BL/6 mice bearing established B16F10 melanomas. Mice that received MYXV-Tred or MYXV-IL15 lived significantly longer than mice given treatment controls. Unexpectedly, the median survival time of MYXV-IL15-treated mice was similar to that of MYXV-treated mice. At 1, 2, and 4 days postinoculation, viral plaque assays detected replicating MYXV-Tred and MYXV-IL15 within treated tumors. At these time points in MYXV-IL15-treated tumors, IL-15 concentration, lymphocyte grades, and cluster of differentiation-3+ cell counts were significantly increased when compared to other treatment groups. However, viral titers, recombinant protein expression, and lymphocyte numbers within the tumors diminished rapidly at 7 days postinoculation. These data indicate that treatment with recombinant MYXV should be repeated at least every 4 days to maintain recombinant protein expression within a murine tumor. Additionally, neutrophilic inflammation was significantly increased in MYXV-Tred- and MYXV-IL15-treated tumors at early time points. It is speculated that neutrophilic inflammation induced by intratumoral

  14. Efficacy of the Oral Fluorouracil Pro-drug Capecitabine in Cancer Treatment: a Review

    OpenAIRE

    John Kouvaris; Haralabos Zabatis; Georgios A. Zacharias; Michael J. Koukourakis; Vassilios Kouloulias; Koukourakis, Georgios V

    2008-01-01

    Abstract: Capecitabine (Xeloda®) was developed as a pro-drug of fluorouracil (FU), with the aim of improving tolerability and intratumor drug concentrations through its tumorspecific conversion to the active drug. The purpose of this paper is to review the available information on capecitabine, focusing on its clinical effectiveness against various carcinomas. Identification of all eligible English trails was made by searching the PubMed and Cochrane databases from 1980 to 2007. Search ter...

  15. Common protein biomarkers assessed by reverse phase protein arrays show considerable intratumoral heterogeneity in breast cancer tissues.

    Science.gov (United States)

    Malinowsky, Katharina; Raychaudhuri, Mithu; Buchner, Theresa; Thulke, Sabrina; Wolff, Claudia; Höfler, Heinz; Becker, Karl-Friedrich; Avril, Stefanie

    2012-01-01

    Proteins are used as prognostic and predictive biomarkers in breast cancer. However, the variability of protein expression within the same tumor is not well studied. The aim of this study was to assess intratumoral heterogeneity in protein expression levels by reverse-phase-protein-arrays (RPPA) (i) within primary breast cancers and (ii) between axillary lymph node metastases from the same patient. Protein was extracted from 106 paraffin-embedded samples from 15 large (≥3 cm) primary invasive breast cancers, including different zones within the primary tumor (peripheral, intermediate, central) as well as 2-5 axillary lymph node metastases in 8 cases. Expression of 35 proteins including 15 phosphorylated proteins representing the HER2, EGFR, and uPA/PAI-1 signaling pathways was assessed using reverse-phase-protein-arrays. All 35 proteins showed considerable intratumoral heterogeneity within primary breast cancers with a mean coefficient of variation (CV) of 31% (range 22-43%). There were no significant differences between phosphorylated (CV 32%) and non-phosphorylated proteins (CV 31%) and in the extent of intratumoral heterogeneity within a defined tumor zone (CV 28%, range 18-38%) or between different tumor zones (CV 24%, range 17-38%). Lymph node metastases from the same patient showed a similar heterogeneity in protein expression (CV 27%, range 18-34%). In comparison, the variation amongst different patients was higher in primary tumors (CV 51%, range 29-98%) and lymph node metastases (CV 65%, range 40-146%). Several proteins showed significant differential expression between different tumor stages, grades, histological subtypes and hormone receptor status. Commonly used protein biomarkers of breast cancer, including proteins from HER2, uPA/PAI-1 and EGFR signaling pathways showed higher than previously reported intratumoral heterogeneity of expression levels both within primary breast cancers and between lymph node metastases from the same patient. Assessment

  16. Interventional Radionuclide Therapy of Hepatocellular Carcinoma:Assessment of Intratumoral Retention of HPMA Copolymers

    Institute of Scientific and Technical Information of China (English)

    YUAN Jian-chao; MIAO Cheng-ping; ZENG Xian-wu; GUO Hong-yun; WANG Xiao-qi; LIAO Shi-qi; XIE Xiao-li

    2013-01-01

    To develop new radiopharmaceuticals for the interventional radionuclide therapy of recurrent hepatocellular carcinoma,poly(HPMA)-APMA-DTPA[HPMA=N-(2-hydroxypropyl) methacrylamide; APMA=N-(3-aminopropyl)methacrylamide; DTPA=diethylenetriaminepentaacetic acid] was synthesized by free radical precipitation polymerization in acetone/dimethylsulfoxide with N,N'-azobis(isobutyronitrile) as the initiator.The copolymers were characterized with nuclear magnetic resonance(NMR) spectroscopy and gel permeation chromatography(GPC,Mn=2.2×104,Mw/Mn=1.38).Subsequently,poly(HPMA)-APMA-DTPA was conjugated with 99mTc radionuclide.Prolonged retention of poly(HPMA)-APMA-DTPA conjugate within the tumor tissues was demonstrated by single-photon emission computed tomography computed tomography(SPECT-CT) at 1,2,4 and 24 h following intra-tumoral injection of the conjugate to hepatocellular carcinoma xenografts in mice.DTPA-99mTC was also synthesized and characterized for comparison.The data suggest that the poly(HPMA)-APMA-DTPA conjugates might be useful for the interventional radionuclide therapy of recurrent hepatocellular carcinoma in humans.

  17. Percutaneous Ethanol Intratumoral Injection for Treatment of Small Primary Liver Cancer:Summary of 240 Cases

    Institute of Scientific and Technical Information of China (English)

    GUOJia; CHENHan; 等

    2002-01-01

    Objective To evaluate the therapeutic effects of percutaneous ethanol intratumoral injection(PETT) for treatment of small primary liver cancer(SPLC). Methods 240 patients with surgically or pathologically proved SPLC(<3 cm in diameter)were treated by PETT(under the guidance of B-ultrasound).Of the 240 patients ,163 had recurrent liver cancer,55 had inoperable liver cancer because of cardiac ,pulmonary ,hepat-ic and renal dydfunctions or due to the close proximity of trmor to the major vessels,and 22 refused to receive surgical resection.In 40 pa-tients who received surgical resection after PETT treatment, the resected tumors were pathologically evaluated for necrotic status and the pa-tients were followed up postoperatively.Results Postoperative1-,2- and 3-year survival rate of the 240 patients was 94.9%,84.2% and 66.3% respectively.Conclusion PETTcan be used as a non-invasive treatment for SPLC,and preoperative PETT appears to be helpful in reducing recurrence of postoperative liver cancer.

  18. Quantitative computed tomographic descriptors associate tumor shape complexity and intratumor heterogeneity with prognosis in lung adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Olya Grove

    Full Text Available Two CT features were developed to quantitatively describe lung adenocarcinomas by scoring tumor shape complexity (feature 1: convexity and intratumor density variation (feature 2: entropy ratio in routinely obtained diagnostic CT scans. The developed quantitative features were analyzed in two independent cohorts (cohort 1: n = 61; cohort 2: n = 47 of patients diagnosed with primary lung adenocarcinoma, retrospectively curated to include imaging and clinical data. Preoperative chest CTs were segmented semi-automatically. Segmented tumor regions were further subdivided into core and boundary sub-regions, to quantify intensity variations across the tumor. Reproducibility of the features was evaluated in an independent test-retest dataset of 32 patients. The proposed metrics showed high degree of reproducibility in a repeated experiment (concordance, CCC≥0.897; dynamic range, DR≥0.92. Association with overall survival was evaluated by Cox proportional hazard regression, Kaplan-Meier survival curves, and the log-rank test. Both features were associated with overall survival (convexity: p = 0.008; entropy ratio: p = 0.04 in Cohort 1 but not in Cohort 2 (convexity: p = 0.7; entropy ratio: p = 0.8. In both cohorts, these features were found to be descriptive and demonstrated the link between imaging characteristics and patient survival in lung adenocarcinoma.

  19. Comparison of detection pattern of HCC by ferumoxide-enhanced MRI and intratumoral blood flow pattern

    Energy Technology Data Exchange (ETDEWEB)

    Itou, Naoki; Kotake, Fumio [Tokyo Medical Coll., Ami, Ibaraki (Japan). Kasumigaura Hospital; Saitou, Kazuhiro; Abe, Kimihiko

    2000-08-01

    We compared the detection rate and pattern of ferumoxide-enhanced magnetic resonance imaging (Fe-MRI) with the intratumoral blood flow pattern determined by CT angiography (CTA) and CT portography (CTAP) in 124 nodes (34 cases) diagnosed as hepatocellular carcinoma (HCC) or borderline HCC, based on the clinical course. Sequences to obtain a T1-weighted images (T1W), proton density-weighted images (PDW), T2-weighted images (T2W), T2*-weighted images (T2*W) were used in Fe-MRI. In nodes shown to be hypervascular on CTA, the detection rate by Fe-MRI was 69.7%. In nodes shown to be avascular by CTAP, the detection rate by Fe-MRI was 67.3%. These rates were higher than with other flow patterns. In nodes showing high signal intensity (HSI) on any sequences, arterial blood flow was increased and portal blood flow decreased in comparison with nodes without high signal intensity. All nodes showing HSI, both on Fe-MRI T2W and T2*W, were hypervascular on CTA, and portal blood flow was absent on CTAP. Nodes showing HSI on both T2*W and T2W were considered to have greater arterial blood flow and decreased portal blood flow compared with nodes appearing as HSI on T2*W, but only as iso- or low signal intensity on T2W (Mann-Whitney U-test; p<0.05). (author)

  20. A simple and effective approach for treatment of situs tumor and metastasis:to promote intratumor pus formation

    Directory of Open Access Journals (Sweden)

    Hong Li

    2015-12-01

    Full Text Available Purpose: The recent emergence of the tumor microenvironment as the critical determinant in cancer outcome opens a new routes to fight cancer, however, the clinical results of targeting microenvironment for treating human cancer have not met expectations. Our purpose is to investigate how to target microenvironment for treatment of situs tumor and metastasis.Methods : We suppose that tumor is a robber from times of anarchy and disorder and can be eradicated in flourishing age. We also suppose that carcinogenesis is largely attributed to physically weak that cann’t get rid of ulcer by pus formation. In vivo,the subcutaneous implant model and pulmonary metastasis model of lewis lung cancer were established. Tumor bearing mice were taken water decoction of Astragalus mongholicus(huangqi and Spina Gleditsiae (zaojiaoci by intragastric administration b.i.d for ten weeks, and the influences of Astragalus mongholicus and Spina Gleditsiae  on tumor progression were evaluated by body temperature,blood oxygen saturation,red cell ATPase,blood  rheology,intratumor hypoxia,capillary permeability, matrix metalloproteinase (MMPs and intratumor pus formation.  Results:We found that both of Astragalus mongholicus and Spina Gleditsiae could keep body temperature,blood oxygen saturation,red cell ATPase and blood rheology,and improve intratumor hypoxia,capillary permeability and MMPs in tumor bearing mice,which led to slower tumor growth and less metastasis. Astragalus mongholicus could remove body poison and stimulate immune responses, and Spina Gleditsiae  could  promote pus formation and proteolytic enzymes. The combination of  Astragalus mongholicus and Spina Gleditsiae favored the restoration of tumor immune responses and proteolytic activity at the tumor site, which not only result to an increase in aseptic pus formation, but also to a decrease in necrotic tissue accumulation, and finally caused a complete intratumor pus

  1. Detection and clinical significance of intratumoral EGFR mutational heterogeneity in Chinese patients with advanced non-small cell lung cancer.

    Directory of Open Access Journals (Sweden)

    Hua Bai

    Full Text Available PURPOSE: This study evaluated occurrence and potential clinical significance of intratumoral EGFR mutational heterogeneity in Chinese patients with non-small cell lung cancer (NSCLC. MATERIALS AND METHODS: Eighty-five stage IIIa-IV NSCLC patients who had undergone palliative surgical resection were included in this study. Of these, 45 patients carried EGFR mutations (group-M and 40 patients were wild-type (group-W. Each tumor sample was microdissected to yield 28-34 tumor foci and Intratumoral EGFR mutation were determined using Denaturing High Performance Liquid Chromatography (DHPLC and Amplification Refractory Mutation System (ARMS. EGFR copy numbers were measured using fluorescence in situ hybridization (FISH. RESULTS: Microdissection yielded 1,431 tumor foci from EGFR mutant patients (group-M and 1,238 foci from wild-type patients (group-W. The EGFR mutant frequencies in group-M were 80.6% (1,154/1,431 and 87.1% (1,247/1,431 using DHPLC and ARMS, respectively. A combination of EGFR-mutated and wild-type cells was detected in 32.9% (28/85 of samples by DHPLC and 28.2% (24/85 by ARMS, supporting the occurrence of intratumoral heterogeneity. Thirty-one patients (36.5% were identified as EGFR FISH-positive. Patients harboring intratumoral mutational heterogeneity possessed lower EGFR copy numbers than those tumors contained mutant cells alone (16.7% vs. 71.0%, P<0.05. Among 26 patients who had received EGFR-TKIs, the mean EGFR mutation content was higher in patients showing partial response (86.1% or stable disease (48.7% compared with patients experiencing progressive disease (6.0% (P = 0.001. There also showed relationship between progression-free survival (PFS and different content of EGFR mutation groups (pure wild type EGFR, EGFR mutation with heterogeneity and pure mutated EGFR (P = 0.001. CONCLUSION: Approximately 30% of patients presented intratumoral EGFR mutational heterogeneity, accompanying with relatively low EGFR copy

  2. Characterization of a new degradation product of nifedipine formed on catalysis by atenolol: A typical case of alteration of degradation pathway of one drug by another.

    Science.gov (United States)

    Handa, Tarun; Singh, Saranjit; Singh, Inder Pal

    2014-02-01

    An increasing interest is being shown throughout the world on the use of fixed-dose combinations of drugs in the therapy of select diseases, like cardiovascular diseases, due to their multiple advantages. Though the main criterion for combining drugs in a single dosage form is the rationale, but consideration like stability of formulation is equally important, due to an added aspect of drug-drug interaction. The objective of this study was to evaluate interaction among the drugs in an antihypertensive combination of nifedipine and atenolol. Nifedipine is a known light sensitive drug, which degrades via intra-molecular mechanisms to nitro- and nitroso-pyridine analogs, along with a few minor secondary products that are formed through inter-molecular interactions amongst primary degradation products and their intermediates. Atenolol is reasonably stable weakly basic drug that is mainly hydrolyzed at acetamide terminal amide moiety to its corresponding carboxylic acid. To the best of our knowledge, there is no known information on chemical compatibility among the two drugs. The present study involved subjecting of nifedipine, atenolol and their combination to a variety of accelerated and stress conditions. HPLC studies revealed formation of a new product in the mixture of two drugs (∼2%), which was also generated from nifedipine alone, but at trace levels (<0.1%). The product was isolated by preparative chromatography and subjected to indepth studies for its characterization. Ultra-violet, FT-IR, mass spectrometric and nuclear magnetic resonance spectroscopic studies highlighted that the principal photo-degradation pathway of nifedipine was modified and diverted in the presence of atenolol. To verify the same, a study was conducted employing two other β-blockers with similar structures to atenolol, and the same product was formed in relatively higher quantity therein also. The new product is postulated to be produced as a result of rearrangement of hydroxylamine

  3. Interventional therapy for human breast cancer in nude mice with 131I gelatin microspheres (131I-GMSs) following intratumoral injection

    International Nuclear Information System (INIS)

    The aim of this study was to investigate the effects of 131I gelatin microspheres (131I-GMS) on human breast cancer cells (MCF-7) in nude mice and the biodistribution of 131I-GMSs following intratumoral injections. A total of 20 tumor-bearing mice were divided into a treatment group and control group and received intratumoral injections of 2.5 mci 131I-GMSs and nonradioactive GMSs, respectively. Tumor size was measured once per week. Another 16 mice received intratumoral injections of 0.4 mci 131I-GMSs and were subjected to single photon emission computed tomography (SPECT) scans and tissue radioactivity concentration measurements on day 1, 4, 8 and 16 postinjection. The 20 tumor-bearing mice received intratumoral injections of 0.4 mci [131I] sodium iodide solution and were subjected to SPECT scans and intratumoral radioactivity measurements at 1, 6, 24, 48 and 72 h postinjection. The tumors were collected for histological examination. The average tumor volume in the 131I-GMSs group on post-treatment day 21 decreased to 86.82 ± 63.6%, while it increased to 893.37 ± 158.12% in the control group (P < 0.01 vs. the 131I-GMSs group). 131I-GMSs provided much higher intratumoral retention of radioactivity, resulting in 19.93 ± 5.24% of the injected radioactivity after 16 days, whereas the control group retained only 1.83 ± 0.46% of the injected radioactivity within the tumors at 1 h postinjection. 131I-GMSs suppressed the growth of MCF-7 in nude mice and provided sustained intratumoral radioactivity retention. The results suggest the potential of 131I-GMSs for clinical applications in radiotherapy for breast cancer

  4. A Novel Drug Delivery System for Osteosarcoma Chemotherapy

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    A thermo-responsive chitosan hydrogel system (TRCHS) was prepared by chitosan ( CS ) andβ- glycerophosphate ( β- GP ) to deliver Adriamycin (ADM) locally for curing osteosarcoma . Release property was investigated by release experiments in vitro and results show that it can be applied to local drug release because it is able to release drug at high concentration for 17 days. The treatment effect was studied by injecting intratumorally to osteosarcoma tumors ( CRL- 1427) implanted subcutaneously on Specific Pathogen-free (SPF) mice. The statistical analytical results show that TRCHS delivering ADM is more efficacious than saline intratumoral injection,which loads the same quantity of ADM , but is less poisonous. Based on the analysis above, this novel biodegradable polymer implant is an effective and safe vehicle for sustained local delivery of ADM, and is supposed to be applied in neoadjuvant chemotherapy for osteosarcoma.

  5. In Vitro Resistance Selections for Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors Give Mutants with Multiple Point Mutations in the Drug-binding Site and Altered Growth*

    OpenAIRE

    Ross, Leila S.; Gamo, Francisco Javier; Lafuente-Monasterio, Maria José; Singh, Onkar M. P.; Rowland, Paul; Wiegand, Roger C.; Wirth, Dyann F

    2014-01-01

    Malaria is a preventable and treatable disease; yet half of the world's population lives at risk of infection, and an estimated 660,000 people die of malaria-related causes every year. Rising drug resistance threatens to make malaria untreatable, necessitating both the discovery of new antimalarial agents and the development of strategies to identify and suppress the emergence and spread of drug resistance. We focused on in-development dihydroorotate dehydrogenase (DHODH) inhibitors. Characte...

  6. Intratumoral injection of Propionibacterium acnes suppresses malignant melanoma by enhancing Th1 immune responses.

    Directory of Open Access Journals (Sweden)

    Kenshiro Tsuda

    Full Text Available Malignant melanoma (MM is an aggressive cutaneous malignancy associated with poor prognosis; many putatively therapeutic agents have been administered, but with mostly unsuccessful results. Propionibacterium acnes (P. acnes is an aerotolerant anaerobic gram-positive bacteria that causes acne and inflammation. After being engulfed and processed by phagocytes, P. acnes induces a strong Th1-type cytokine immune response by producing cytokines such as IL-12, IFN-γ and TNF-α. The characteristic Th2-mediated allergic response can be counteracted by Th1 cytokines induced by P. acnes injection. This inflammatory response induced by P. acnes has been suggested to have antitumor activity, but its effect on MM has not been fully evaluated.We analyzed the anti-tumor activity of P. acnes vaccination in a mouse model of MM. Intratumoral administration of P. acnes successfully protected the host against melanoma progression in vivo by inducing both cutaneous and systemic Th1 type cytokine expression, including TNF-α and IFN-γ, which are associated with subcutaneous granuloma formation. P. acnes-treated tumor lesions were infiltrated with TNF-α and IFN-γ positive T cells. In the spleen, TNF-α as well as IFN-γ producing CD8(+T cells were increased, and interestingly, the number of monocytes was also increased following P. acnes administration. These observations suggest that P. acnes vaccination induces both systemic and local antitumor responses. In conclusion, this study shows that P. acnes vaccination may be a potent therapeutic alternative in MM.

  7. Intratumoral injection of taxol in vivo suppresses A549 tumor showing cytoplasmic vacuolization.

    Science.gov (United States)

    Wang, Chaoyang; Chen, Tongsheng

    2012-04-01

    Based on our recent in vitro studies, this report was designed to explore the mechanism by which high concentration of taxol (70 µM) induced paraptosis-like cell death in human lung carcinoma (A549) cells, and to evaluate the therapeutic efficacy of taxol using A549 tumor-bearing mice in vivo. Exposure of cells to taxol induced time-dependent cytotoxicity and cytoplasmic vacuolization without the involvement of Bax, Bak, Mcl-1, Bcl-XL, and caspase-3. Although taxol treatment induced activating transcription factor 6 (ATF6) cleavage indicative of endoplasmic reticulum (ER) stress, silencing ATF6 by shATF6 did not prevent taxol-induced both cytotoxcity and cytoplasmic vacuolization, suggesting that taxol-induced cytoplasmic vacuolization and cell death were not due to ER stress. Moreover, taxol-treated cells did not show DNA fragmentation and loss of mitochondrial membrane potential, the typical characteristics of apoptosis. In addition, taxol-induced cytoplasmic vacuolization did not show the cellular lysis, the characteristics of oncosis, and positive of β-galactosidase, the characteristic of senescence, indicating that taxol induced paraptosis-like cell death is neither oncosis nor senescence. Moreover, our in vivo data showed that intratumoral injection of taxol (50 mg/kg) in A549 tumor xenograft mice on day 1 and day 19 potently suppressed tumor growth showing significant ER vacuolization without toxicity. In conclusion, high concentration of taxol exhibits a significant anticancer activity by inducing paraptosis-like cell death in vitro and in vivo, without significant toxicity, suggesting a promising therapeutic strategy for apoptosis-resistance cancer by inducing ER vacuolization.

  8. A Time-Based and Intratumoral Proteomic Assessment of a Recurrent Glioblastoma Multiforme

    Science.gov (United States)

    de Aquino, Priscila F.; Carvalho, Paulo Costa; Nogueira, Fábio C. S.; da Fonseca, Clovis Orlando; de Souza Silva, Júlio Cesar Thomé; Carvalho, Maria da Gloria da Costa; Domont, Gilberto B.; Zanchin, Nilson I. T.; Fischer, Juliana de Saldanha da Gama

    2016-01-01

    Tumors consist of cells in different stages of transformation with molecular and cellular heterogeneity. By far, heterogeneity is the hallmark of glioblastoma multiforme (GBM), the most malignant and aggressive type of glioma. Most proteomic studies aim in comparing tumors from different patients, but here we dive into exploring the intratumoral proteome diversity of a single GBM. For this, we profiled tumor fragments from the profound region of the same patient’s GBM but obtained from two surgeries a year’s time apart. Our analysis also included GBM‘s fragments from different anatomical regions. Our quantitative proteomic strategy employed 4-plex iTRAQ peptide labeling followed by a four-step strong cation chromatographic separation; each fraction was then analyzed by reversed-phase nano-chromatography coupled on-line with an Orbitrap-Velos mass spectrometer. Unsupervised clustering grouped the proteomic profiles into four major distinct groups and showed that most changes were related to the tumor’s anatomical region. Nevertheless, we report differentially abundant proteins from GBM’s fragments of the same region but obtained 1 year apart. We discuss several key proteins (e.g., S100A9) and enriched pathways linked with GBM such as the Ras pathway, RHO GTPases activate PKNs, and those related to apoptosis, to name a few. As far as we know, this is the only report that compares GBM fragments proteomic profiles from the same patient. Ultimately, our results fuel the forefront of scientific discussion on the importance in exploring the richness of subproteomes within a single tissue sample for a better understanding of the disease, as each tumor is unique. PMID:27597932

  9. Increased radiosensitivity of colorectal tumors with intra-tumoral injection of low dose of gold nanoparticles

    Science.gov (United States)

    Shi, Minghan; Paquette, Benoit; Thippayamontri, Thititip; Gendron, Louis; Guérin, Brigitte; Sanche, Léon

    2016-01-01

    The potential of gold nanoparticles (GNPs) as radiosensitizers for the treatment of malignant tumors has been limited by the large quantities of GNPs that must be administered and the requirement for low-energy X-ray irradiation to optimize radiosensitization. In this study, we enhance the radiosensitivity of HCT116 human colorectal cells with tiopronin-coated GNPs (Tio-GNPs) combined with a low-energy X-ray (26 keV effective energy) source, similar to the Papillon 50 clinical irradiator used for topical irradiation of rectal tumors. Sensitizer enhancement ratios of 1.48 and 1.69 were measured in vitro, when the HCT116 cells were incubated with 0.1 mg/mL and 0.25 mg/mL of Tio-GNPs, respectively. In nude mice bearing the HCT116 tumor, intra-tumoral (IT) injection of Tio-GNPs allowed a 94 times higher quantity of Tio-GNPs to accumulate than was possible by intravenous injection and facilitated a significant tumor response. The time following irradiation, for tumors growing to four times their initial tumor volume (4Td) was 54 days for the IT injection of 366.3 μg of Tio-GNPs plus 10 Gy, compared to 37 days with radiation alone (P=0.0018). Conversely, no significant improvement was obtained when GNPs were injected intravenously before tumor irradiation (P=0.6547). In conclusion, IT injection of Tio-GNPs combined with low-energy X-rays can significantly reduce the growth of colorectal tumors.

  10. Experimental study on ultrasound-guided intratumoral injection of "Star-99" in treatment of hepatocellular carcinoma of nude mice

    Institute of Scientific and Technical Information of China (English)

    Li-Wu Lin; Xiao-Dong Lin; Yi-Mi He; Shang-Da Gao; En-Sheng Xue

    2003-01-01

    AIM: To investigate the anti-cancer effect and the immunological mechanism of ultrasound-guided intratumoral injection of Chinese medicine "Star-99" in hepatocellular carcinoma (HCC) of nude mice.METHODS: Twenty-eight human hepatocellular carcinoma SMMC-7721 transplanted nude mice, 14 of hypodermically implanted and 14 of orthotopic liver transplanted, were randomly divided into three groups of which 14 mice with Star-99, and 7 with ethanol and saline respectively. Ten days after the transplantation the medicines were injected into the tumors of all the nude mice once every 5 days.After 4 injections the nude mice were killed. The diameters of three dimension of the tumors were measured by high frequency ultrasound before and after the treatment and the tumor growth indexes* (TGI) were calculated.Radioimmunoassay was used to detect the serum levels of interleukin-2 (IL-2) and tumor necrosis factor (TNF)-alpha.The tumor tissues were sent for flow cytometry (FCM) DNA analysis. Apoptotic cells were visualized by TUNEL assay.All the experiments were carried out by double blind method. zRESULTS: The TGI of Star-99 group (0.076±0.024) was markedly lower than that of the saline group (4.654±1.283)(P<0.01). It also seemed to be lower than that of the ethanol group (0.082±0.028), but not significantly different (P>0.05).Serum levels of IL-2 and TNF-α were markedly higher than those of ethanol group and saline groups (P<0.05). The mean apoptotic index (AI: percentage of TUNEL signal positive cells)in Star-99 group (48.98±5.09 %) was significantly higher than that of the ethanol group (11.95±2.24 %) and the saline group (10.48±3.85 %) (P<0.01). FCM DNA analysis showed that the appearance rate of the apoptosis peak in Srar-99group was 92.9 %, markedly higher than that of the ethanol group (14.3 %) and the saline group (0.0 %) (P<0.01).Correlation (r=0.499, P<0.05) was found between AI and serum level of TNF-α.CONCLUSION: Star-99 has an effect on the

  11. Salivary gland tumors of the parotid gland: CT and MR imaging findings with emphasis on intratumoral cystic components

    Energy Technology Data Exchange (ETDEWEB)

    Kato, Hiroki; Watanabe, Haruo [Gifu University School of Medicine, Department of Radiology, Gifu (Japan); Kanematsu, Masayuki [Gifu University School of Medicine, Department of Radiology, Gifu (Japan); Gifu University Hospital, High-Level Imaging Diagnosis Center, Gifu (Japan); Mizuta, Keisuke; Aoki, Mitsuhiro [Gifu University School of Medicine, Department of Otolaryngology, Gifu (Japan)

    2014-09-15

    The purpose of this study was to assess computed tomography (CT) and magnetic resonance (MR) imaging findings of salivary gland tumors of the parotid gland with emphasis on intratumoral cystic components. Seventy-two histopathologically confirmed salivary gland tumors of the parotid gland (44 benign and 28 malignant), which underwent both CT and MR imaging including contrast-enhanced study, were included in this study. We retrospectively reviewed images for the presence, number, occupying rate, margin characteristics, distribution, and predominant MR signal intensity of intratumoral cystic components. The prevalence of cystic components was greater in malignant than benign tumors (79 vs. 50 %, p < 0.05). The number and occupying rate were similar between benign and malignant tumors. The irregular margins were more frequent in malignant than benign tumors (73 vs. 27 %, p < 0.01). The frequency of eccentric location was greater in benign than malignant tumors (91 vs. 55 %, p < 0.01), whereas the frequency of centric location was greater in malignant than benign tumors (32 vs. 0 %, p < 0.01). On T1-weighted images, the frequency of hyperintensity was greater in benign than malignant tumors (50 vs. 9 %, p < 0.01), whereas that of isointensity was greater in malignant than benign tumors (50 vs. 0 %, p < 0.01). Multiple logistic regression analysis showed that the absence of irregular margins of cystic components only was significantly correlated with the presence of benign salivary gland tumors (p < 0.01). Imaging features of intratumoral cystic components may help to differentiate benign from malignant tumors of the parotid salivary gland. (orig.)

  12. High resolution SPECT imaging for visualization of intratumoral heterogeneity using a SPECT/CT scanner dedicated for small animal imaging

    International Nuclear Information System (INIS)

    Tumor interiors are never homogeneous and in vivo visualization of intratumoral heterogeneity would be an innovation that contributes to improved cancer therapy. But, conventional nuclear medicine tests have failed to visualize heterogeneity in vivo because of limited spatial resolution. Recently developed single photon emission computed tomographic (SPECT) scanners dedicated for small animal imaging are of interest due to their excellent spatial resolution of 111In and simulations of actual small animal imaging. The optimal conditions obtained were validated by in vivo imaging of sarcoma 180-bearing mice. Larger number of counts must be obtained within limited acquisition time to visualize tumor heterogeneity in vivo in animal imaging, compared to cases that simply detect tumors. At an acquisition time of 30 min, better image quality was obtained with pinhole apertures diameter of 1.4 mm than of 1.0 mm. The obtained best spatial resolution was 1.3 mm, it was acceptable for our purpose, though a little worse than the best possible performance of the scanner (1.0 mm). Additionally, the reconstruction parameters, such as noise suppression, voxel size, and iteration/subset number, needed to be optimized under the limited conditions and were different from those found under the ideal condition. The minimal radioactivity concentration for visualization of heterogeneous tumor interiors was estimated to be as high as 0.2-0.5 MBq/mL. Liposomes containing 111In met this requirement and were administered to tumor-bearing mice. SPECT imaging successfully showed heterogeneous 111In distribution within the tumors in vivo with good spatial resolution. A threshold of 0.2 MBq/g for clear visualization of tumor heterogeneity was validated. Autoradiograms obtained ex vivo of excised tumors confirmed that the in vivo SPECT images accurately depicted the heterogeneous intratumoral accumulation of liposomes. Intratumoral heterogeneity was successfully visualized under the optimized

  13. Inhibition of GSK-3β activity can result in drug and hormonal resistance and alter sensitivity to targeted therapy in MCF-7 breast cancer cells

    OpenAIRE

    Sokolosky, Melissa; Chappell, William H.; Stadelman, Kristin; Abrams, Stephen L.; Davis, Nicole M.; Steelman, Linda S.; McCubrey, James A.

    2014-01-01

    The PI3K/Akt/mTORC1 pathway plays prominent roles in malignant transformation, prevention of apoptosis, drug resistance, and metastasis. One molecule regulated by this pathway is GSK-3β. GSK-3β is phosphorylated by Akt on S9, which leads to its inactivation; however, GSK-3β also can regulate the activity of the PI3K/Akt/mTORC1 pathway by phosphorylating molecules such as PTEN, TSC2, p70S6K, and 4E-BP1. To further elucidate the roles of GSK-3β in chemotherapeutic drug and hormonal resistance o...

  14. Common protein biomarkers assessed by reverse phase protein arrays show considerable intratumoral heterogeneity in breast cancer tissues.

    Directory of Open Access Journals (Sweden)

    Katharina Malinowsky

    Full Text Available Proteins are used as prognostic and predictive biomarkers in breast cancer. However, the variability of protein expression within the same tumor is not well studied. The aim of this study was to assess intratumoral heterogeneity in protein expression levels by reverse-phase-protein-arrays (RPPA (i within primary breast cancers and (ii between axillary lymph node metastases from the same patient. Protein was extracted from 106 paraffin-embedded samples from 15 large (≥3 cm primary invasive breast cancers, including different zones within the primary tumor (peripheral, intermediate, central as well as 2-5 axillary lymph node metastases in 8 cases. Expression of 35 proteins including 15 phosphorylated proteins representing the HER2, EGFR, and uPA/PAI-1 signaling pathways was assessed using reverse-phase-protein-arrays. All 35 proteins showed considerable intratumoral heterogeneity within primary breast cancers with a mean coefficient of variation (CV of 31% (range 22-43%. There were no significant differences between phosphorylated (CV 32% and non-phosphorylated proteins (CV 31% and in the extent of intratumoral heterogeneity within a defined tumor zone (CV 28%, range 18-38% or between different tumor zones (CV 24%, range 17-38%. Lymph node metastases from the same patient showed a similar heterogeneity in protein expression (CV 27%, range 18-34%. In comparison, the variation amongst different patients was higher in primary tumors (CV 51%, range 29-98% and lymph node metastases (CV 65%, range 40-146%. Several proteins showed significant differential expression between different tumor stages, grades, histological subtypes and hormone receptor status. Commonly used protein biomarkers of breast cancer, including proteins from HER2, uPA/PAI-1 and EGFR signaling pathways showed higher than previously reported intratumoral heterogeneity of expression levels both within primary breast cancers and between lymph node metastases from the same patient

  15. Alternating treatment with didanosine and zidovudine versus either drug alone for the treatment of advanced HIV infection. The Alter Study. Nordic HIV Therapy Group

    DEFF Research Database (Denmark)

    Gerstoft, J; Melander, H; Bruun, J N;

    1997-01-01

    The efficacy and safety of an alternating regime with zidovudine and didanosine versus treatment with either drug alone were investigated in a randomized, open, controlled trial, 552 patients with advanced HIV infection, 47% of whom had received prior treatment with zidovudine, were enrolled...

  16. Prenatal Stress Alters Progestogens to Mediate Susceptibility to Sex-Typical, Stress-Sensitive Disorders, such as Drug Abuse: A Review

    OpenAIRE

    Frye, Cheryl A.; Paris, Jason J.; Osborne, Danielle M.; Campbell, Joannalee C.; Kippin, Tod E.

    2011-01-01

    Maternal–offspring interactions begin prior to birth. Experiences of the mother during gestation play a powerful role in determining the developmental programming of the central nervous system. In particular, stress during gestation alters developmental programming of the offspring resulting in susceptibility to sex-typical and stress-sensitive neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. However, neither these effects, nor the underlying mechanisms, are well underst...

  17. Prenatal stress alters progestogens to mediate susceptibility to sex-typical, stress-sensitive disorders, such as drug abuse: a review

    OpenAIRE

    Frye, Cheryl A.; Paris, Jason J.; Danielle eOsborne; Joanna eCampbell; Tod eKippin

    2011-01-01

    Maternal-offspring interactions begin prior to birth. Experiences of the mother during gestation play a powerful role in determining the developmental programming of the central nervous system. In particular, stress during gestation alters developmental programming of the offspring resulting in susceptibility to sex-typical and stress-sensitive neurodevelopmental, neuropsychiatric and neurodegenerative disorders. However, neither these effects, nor the underlying mechanisms, are well unders...

  18. In vitro resistance selections for Plasmodium falciparum dihydroorotate dehydrogenase inhibitors give mutants with multiple point mutations in the drug-binding site and altered growth.

    Science.gov (United States)

    Ross, Leila S; Gamo, Francisco Javier; Lafuente-Monasterio, Maria José; Singh, Onkar M P; Rowland, Paul; Wiegand, Roger C; Wirth, Dyann F

    2014-06-27

    Malaria is a preventable and treatable disease; yet half of the world's population lives at risk of infection, and an estimated 660,000 people die of malaria-related causes every year. Rising drug resistance threatens to make malaria untreatable, necessitating both the discovery of new antimalarial agents and the development of strategies to identify and suppress the emergence and spread of drug resistance. We focused on in-development dihydroorotate dehydrogenase (DHODH) inhibitors. Characterizing resistance pathways for antimalarial agents not yet in clinical use will increase our understanding of the potential for resistance. We identified resistance mechanisms of Plasmodium falciparum (Pf) DHODH inhibitors via in vitro resistance selections. We found 11 point mutations in the PfDHODH target. Target gene amplification and unknown mechanisms also contributed to resistance, albeit to a lesser extent. These mutant parasites were often hypersensitive to other PfDHODH inhibitors, which immediately suggested a novel combination therapy approach to preventing resistance. Indeed, a combination of wild-type and mutant-type selective inhibitors led to resistance far less often than either drug alone. The effects of point mutations in PfDHODH were corroborated with purified recombinant wild-type and mutant-type PfDHODH proteins, which showed the same trends in drug response as the cognate cell lines. Comparative growth assays demonstrated that two mutant parasites grew less robustly than their wild-type parent, and the purified protein of those mutants showed a decrease in catalytic efficiency, thereby suggesting a reason for the diminished growth rate. Co-crystallography of PfDHODH with three inhibitors suggested that hydrophobic interactions are important for drug binding and selectivity.

  19. Intratumoral convergence of the TCR repertoires of effector and Foxp3+ CD4+ T cells.

    Directory of Open Access Journals (Sweden)

    Michal Kuczma

    Full Text Available The presence of Foxp3(+ regulatory CD4(+ T cells in tumor lesions is considered one of the major causes of ineffective immune response in cancer. It is not clear whether intratumoral T(reg cells represent T(reg cells pre-existing in healthy mice, or arise from tumor-specific effector CD4(+ T cells and thus representing adaptive T(reg cells. The generation of T(reg population in tumors could be further complicated by recent evidence showing that both in humans and mice the peripheral population of T(reg cells is heterogenous and consists of subsets which may differentially respond to tumor-derived antigens. We have studied T(reg cells in cancer in experimental mice that express naturally selected, polyclonal repertoire of CD4(+ T cells and which preserve the heterogeneity of the T(reg population. The majority of T(reg cells present in healthy mice maintained a stable suppressor phenotype, expressed high level of Foxp3 and an exclusive set of TCRs not used by naive CD4(+ T cells. A small T(reg subset, utilized TCRs shared with effector T cells and expressed a lower level of Foxp3. We show that response to tumor-derived antigens induced efficient clonal recruitment and expansion of antigen-specific effector and T(reg cells. However, the population of T(reg cells in tumors was dominated by cells expressing TCRs shared with effector CD4(+ T cells. In contrast, T(reg cells expressing an exclusive set of TCRs, that dominate in healthy mice, accounted for only a small fraction of all T(reg cells in tumor lesions. Our results suggest that the T(reg repertoire in tumors is generated by conversion of effector CD4(+ T cells or expansion of a minor subset of T(reg cells. In conclusion, successful cancer immunotherapy may depend on the ability to block upregulation of Foxp3 in effector CD4(+ T cells and/or selectively inhibiting the expansion of a minor T(reg subset.

  20. Alteration of Drug Sensitivity in Human Colon Cancer Cells after Exposure to Heat: Implications for Liver Metastasis Therapy using RFA and Chemotherapy

    OpenAIRE

    Makizumi, Ryouji; Yang, Weng-Lang; Owen, Randall P.; Sharma, Rohit R.; Ravikumar, T S

    2008-01-01

    Radiofrequency ablation (RFA) is gaining popularity for treating colorectal liver metastases by inducing image guided tumor hyperthermia. In order to reduce tumor recurrence, adjuvant therapies have been administered post-RFA. We hypothesized that tumor cells escaping RFA cytotoxicity by being in the sublethal zones of tumor might develop differential behavior toward cytotoxic drugs. Here, we used cultured human colorectal cancer cells to evaluate the interaction between heat treatment and ch...

  1. Knockout of P-glycoprotein does not alter antiepileptic drug efficacy in the intrahippocampal kainate model of mesial temporal lobe epilepsy in mice.

    Science.gov (United States)

    Bankstahl, Marion; Klein, Sabine; Römermann, Kerstin; Löscher, Wolfgang

    2016-10-01

    Pharmacoresistance to antiepileptic drugs (AEDs) is a major challenge in epilepsy therapy, affecting at least 30% of patients. Thus, there is considerable interest in the mechanisms responsible for such pharmacoresistance, with particular attention on the specific cellular and molecular factors that lead to reduced drug sensitivity. Current hypotheses of refractory epilepsy include the multidrug transporter hypothesis, which posits that increased expression or function of drug efflux transporters, such as P-glycoprotein (Pgp), in brain capillaries reduces the local concentration of AEDs in epileptic brain regions to subtherapeutic levels. In the present study, this hypothesis was addressed by evaluating the efficacy of six AEDs in wildtype and Pgp deficient Mdr1a/b(-/-) mice in the intrahippocampal kainate model of mesial temporal lobe epilepsy. In this model, frequent focal electrographic seizures develop after an initial kainate-induced status epilepticus. These seizures are resistant to major AEDs, but the mechanisms of this resistance are unknown. In the present experiments, the focal nonconvulsive seizures were resistant to carbamazepine and phenytoin, whereas high doses of valproate and levetiracetam exerted moderate and phenobarbital and diazepam marked anti-seizure effects. All AEDs suppressed generalized convulsive seizures. No significant differences between wildtype and Pgp-deficient mice were observed in anti-seizure drug efficacies. Also, the individual responder and nonresponder rates in each experiment did not differ between mouse genotypes. This does not argue against the multidrug transporter hypothesis in general, but indicates that Pgp is not involved in the mechanisms explaining that focal electrographic seizures are resistant to some AEDs in the intrahippocampal mouse model of partial epilepsy. This was substantiated by the finding that epileptic wildtype mice do not exhibit increased Pgp expression in this model. PMID:27288003

  2. THE THERAPEUTIC EFFECT OF INTRATUMORAL INJECTION OF GM-CSF GENE-MODIFIED ALLOGENIC MACROPHAGES ON TUMOR-BEARING MICE

    Institute of Scientific and Technical Information of China (English)

    Yu Yizhi; Cao Xuetao; Lei Hong; Wang Quanxing; Tao Qun

    1998-01-01

    Both the antigen presenting ability and the cytotoxicity of macrophages can be enhanced by GM-CSF gene transfer. In the present study, the therapeutic effect of intratumoral injection with GM-CSF gene-modified allogenic macrophages on tumor-bearing mice observed.The peritoneal macrophages of C57BL/6 mice were transfected with GM-CSF gene mediated by recombinant adenovirus and the subcutaneous CT26 colon adenocarcinoma-bearing BALB/c mice were treated by intratumoral injection of the above macrophages. The survival time of the tumor-bearing mice were prolonged significantly and some tumor mass disappeared completely. The necroses of the tumor cells and massive infiltration of inflammatory cells were observed 6 days after treatment.30 days after treatment, only the leftover of tumor cells and the inflammatory cells remained. The data indicated that introtumoral injection of GM-CSF gene-modified allogenic macrophages displayed more potent therapeutic effect on the preestablished tumor-bearing mice.

  3. Altered regional brain volumes in elderly carriers of a risk variant for drug abuse in the dopamine D2 receptor gene (DRD2).

    Science.gov (United States)

    Roussotte, Florence F; Jahanshad, Neda; Hibar, Derrek P; Thompson, Paul M

    2015-06-01

    Dopamine D2 receptors mediate the rewarding effects of many drugs of abuse. In humans, several polymorphisms in DRD2, the gene encoding these receptors, increase our genetic risk for developing addictive disorders. Here, we examined one of the most frequently studied candidate variant for addiction in DRD2 for association with brain structure. We tested whether this variant showed associations with regional brain volumes across two independent elderly cohorts, totaling 1,032 subjects. We first examined a large sample of 738 elderly participants with neuroimaging and genetic data from the Alzheimer's Disease Neuroimaging Initiative (ADNI1). We hypothesized that this addiction-related polymorphism would be associated with structural brain differences in regions previously implicated in familial vulnerability for drug dependence. Then, we assessed the generalizability of our findings by testing this polymorphism in a non-overlapping replication sample of 294 elderly subjects from a continuation of the first ADNI project (ADNI2) to minimize the risk of reporting false positive results. In both cohorts, the minor allele-previously linked with increased risk for addiction-was associated with larger volumes in various brain regions implicated in reward processing. These findings suggest that neuroanatomical phenotypes associated with familial vulnerability for drug dependence may be partially mediated by DRD2 genotype.

  4. Relationship between intratumoral expression of genes coding for xenobiotic-metabolizing enzymes and benefit from adjuvant tamoxifen in estrogen receptor alpha-positive postmenopausal breast carcinoma

    International Nuclear Information System (INIS)

    Little is known of the function and clinical significance of intratumoral dysregulation of xenobiotic-metabolizing enzyme expression in breast cancer. One molecular mechanism proposed to explain tamoxifen resistance is altered tamoxifen metabolism and bioavailability. To test this hypothesis, we used real-time quantitative RT-PCR to quantify the mRNA expression of a large panel of genes coding for the major xenobiotic-metabolizing enzymes (12 phase I enzymes, 12 phase II enzymes and three members of the ABC transporter family) in a small series of normal breast (and liver) tissues, and in estrogen receptor alpha (ERα)-negative and ERα-positive breast tumors. Relevant genes were further investigated in a well-defined cohort of 97 ERα-positive postmenopausal breast cancer patients treated with primary surgery followed by adjuvant tamoxifen alone. Seven of the 27 genes showed very weak or undetectable expression in both normal and tumoral breast tissues. Among the 20 remaining genes, seven genes (CYP2A6, CYP2B6, FMO5, NAT1, SULT2B1, GSTM3 and ABCC11) showed significantly higher mRNA levels in ERα-positive breast tumors than in normal breast tissue, or showed higher mRNA levels in ERα-positive breast tumors than in ERα-negative breast tumors. In the 97 ERα-positive breast tumor series, most alterations of these seven genes corresponded to upregulations as compared with normal breast tissue, with an incidence ranging from 25% (CYP2A6) to 79% (NAT1). Downregulation was rare. CYP2A6, CYP2B6, FMO5 and NAT1 emerged as new putative ERα-responsive genes in human breast cancer. Relapse-free survival was longer among patients with FMO5-overexpressing tumors or NAT1-overexpressing tumors (P = 0.0066 and P = 0.000052, respectively), but only NAT1 status retained prognostic significance in Cox multivariate regression analysis (P = 0.0013). Taken together, these data point to a role of genes coding for xenobiotic-metabolizing enzymes in breast tumorigenesis, NAT1 being an

  5. Patients treated for male pattern hair with finasteride show, after discontinuation of the drug, altered levels of neuroactive steroids in cerebrospinal fluid and plasma.

    Science.gov (United States)

    Caruso, Donatella; Abbiati, Federico; Giatti, Silvia; Romano, Simone; Fusco, Letizia; Cavaletti, Guido; Melcangi, Roberto Cosimo

    2015-02-01

    Observations performed in a subset of patients treated for male pattern hair loss indicate that persistent sexual side effects as well as anxious/depressive symptomatology have been reported even after discontinuation of finasteride treatment. Due to the capability of finasteride to block the metabolism of progesterone (PROG) and/or testosterone (T) we have evaluated, by liquid chromatography-tandem mass spectrometry, the levels of several neuroactive steroids in paired plasma and cerebrospinal fluid (CSF) samples obtained from post-finasteride patients and in healthy controls. At the examination, post-finasteride patients reported muscular stiffness, cramps, tremors and chronic fatigue in the absence of clinical evidence of any muscular disorder or strength reduction. Although severity of the anxious/depressive symptoms was quite variable in their frequency, overall all the subjects had a fairly complex and constant neuropsychiatric pattern. Assessment of neuroactive steroid levels in CSF showed a decrease of PROG and its metabolites, dihydroprogesterone (DHP) and tetrahydroprogesterone (THP), associated with an increase of its precursor pregnenolone (PREG). Altered levels were also observed for T and its metabolites. Thus, a significant decrease of dihydrotestosterone (DHT) associated with an increase of T as well as of 3α-diol was detected. Changes in neuroactive steroid levels also occurred in plasma. An increase of PREG, T, 3α-diol, 3β-diol and 17β-estradiol was associated with decreased levels of DHP and THP. The present observations show that altered levels of neuroactive steroids, associated with depression symptoms, are present in androgenic alopecia patients even after discontinuation of the finasteride treatment. This article is part of a Special Issue entitled 'Sex steroids and brain disorders'. PMID:24717976

  6. Transdermal drug targeting and functional imaging of tumor blood vessels in the mouse auricle.

    Science.gov (United States)

    Schröder, Hannes; Komljenovic, Dorde; Hecker, Markus; Korff, Thomas

    2016-02-01

    Subcutaneously growing tumors are widely utilized to study tumor angiogenesis and the efficacy of antiangiogenic therapies in mice. To additionally assess functional and morphologic alterations of the vasculature in the periphery of a growing tumor, we exploited the easily accessible and hierarchically organized vasculature of the mouse auricle. By site-specific subcutaneous implantation of a defined preformed mouse B16/F0 melanoma aggregate, a solid tumor nodule developed within 14 d. Growth of the tumor nodule was accompanied by a 4-fold increase in its perfusion as well as a 2- to 4-fold elevated diameter and perfusion of peripheral blood vessels that had connected to the tumor capillary microvasculature. By transdermal application of the anticancer drug bortezomib, tumor growth was significantly diminished by about 50% without provoking side effects. Moreover, perfusion and tumor microvessel diameter as well as growth and perfusion of arterial or venous blood vessels supplying or draining the tumor microvasculature were decreased under these conditions by up to 80%. Collectively, we observed that the progressive tumor growth is accompanied by the enlargement of supplying and draining extratumoral blood vessels. This process was effectively suppressed by bortezomib, thereby restricting the perfusion capacity of both extra and intratumoral blood vessels. PMID:26546130

  7. Intratumoral Heterogeneity of Breast Cancer Xenograft Models: Texture Analysis of Diffusion-Weighted MR Imaging

    Energy Technology Data Exchange (ETDEWEB)

    Yun, Bo La; Cho, Nariya; Li, Mulun; Song, In Chan; Moon, Woo Kyung [Dept. of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul (Korea, Republic of); Jang, Min Hye; Park, So Yeon; Kim, Bo Young [Seoul National University Bundang Hospital, Seongnam (Korea, Republic of); Kang, Ho Chul [Dept. of Computer Science and Engineering, Seoul National University, Seoul (Korea, Republic of)

    2014-10-15

    .464), kurtosis (r = -0.581, r = -0.389), contrast (r = -0.473, r = -0.549) and COR (r = 0.588, r = 0.580) correlated with MVDmean and MVDdiff (p < 0.05 for all). The texture analysis of ADC maps may help to determine the intratumoral spatial heterogeneity of necrosis patterns, amount of cellular proliferation and the vascularity in MCF-7 and MDA-MB-231 xenograft breast cancer models.

  8. Immune-mediated regression of established B16F10 melanoma by intratumoral injection of attenuated Toxoplasma gondii protects against rechallenge

    OpenAIRE

    Baird, Jason R; Byrne, Katelyn T.; Lizotte, Patrick H; Toraya-Brown, Seiko; Scarlett, Uciane K.; Alexander, Matthew P.; Sheen, Mee Rie; Fox, Barbara A.; Bzik, David J.; Bosenberg, Marcus; Mullins, David W.; Turk, Mary Jo; Fiering, Steven

    2012-01-01

    Immune recognition of tumors can limit cancer development, but antitumor immune responses are often blocked by tumor-mediated immunosuppression. Since microbes or microbial constituents are powerful adjuvants to stimulate immune responses, we evaluated whether intratumoral administration of a highly immunogenic but attenuated parasite could induce rejection of an established poorly immunogenic tumor.

  9. Differentiating intratumoral melanocytes from Langerhans cells in nonmelanocytic pigmented skin tumors in vivo by label-free third-harmonic generation microscopy

    Science.gov (United States)

    Weng, Wei-Hung; Liao, Yi-Hua; Tsai, Ming-Rung; Wei, Ming-Liang; Huang, Hsin-Yi; Sun, Chi-Kuang

    2016-07-01

    Morphology and distribution of melanocytes are critical imaging information for the diagnosis of melanocytic lesions. However, how to image intratumoral melanocytes noninvasively in pigmented skin tumors is seldom investigated. Third-harmonic generation (THG) is shown to be enhanced by melanin, whereas high accuracy has been demonstrated using THG microscopy for in vivo differential diagnosis of nonmelanocytic pigmented skin tumors. It is thus desirable to investigate if label-free THG microscopy was capable to in vivo identify intratumoral melanocytes. In this study, histopathological correlations of label-free THG images with the immunohistochemical images stained with human melanoma black (HMB)-45 and cluster of differentiation 1a (CD1a) were made. The correlation results indicated that the intratumoral THG-bright dendritic-cell-like signals were endogenously derived from melanocytes rather than Langerhans cells (LCs). The consistency between THG-bright dendritic-cell-like signals and HMB-45 melanocyte staining showed a kappa coefficient of 0.807, 84.6% sensitivity, and 95% specificity. In contrast, a kappa coefficient of -0.37, 21.7% sensitivity, and 30% specificity were noted between the THG-bright dendritic-cell-like signals and CD1a staining for LCs. Our study indicates the capability of noninvasive label-free THG microscopy to differentiate intratumoral melanocytes from LCs, which is not feasible in previous in vivo label-free clinical-imaging modalities.

  10. Pilot study of intratumoral injection of recombinant heat shock protein 70 in the treatment of malignant brain tumors in children

    Directory of Open Access Journals (Sweden)

    Shevtsov MA

    2014-06-01

    Full Text Available Maxim A Shevtsov,1,2 Alexander V Kim,2 Konstantin A Samochernych,2 Irina V Romanova,3 Boris A Margulis,1 Irina V Guzhova,1 Igor V Yakovenko,2 Alexander M Ischenko,4 William A Khachatryan2 1Institute of Cytology of the Russian Academy of Sciences, 2AL Polenov Russian Research Scientific Institute of Neurosurgery, 3IM Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 4Research Institute of Highly Pure Biopreparations, St Petersburg, Russian Federation Abstract: Intratumoral injections of recombinant heat shock protein (Hsp70 were explored for feasibility in patients with brain tumors. Patients aged 4.5–14 years with untreated newly diagnosed tumors (n=12 were enrolled. After tumor resection, five injections of recombinant Hsp70 (total 2.5 mg were administered into the resection cavity through a catheter. Before administration of Hsp70 and after the last injection, specific immune responses to the autologous tumor lysate were evaluated using the delayed-type hypersensitivity test. Further, peripheral blood was monitored to identify possible changes in lymphocyte subpopulations, cytokine levels, and the cytolytic activity of natural killer cells. The follow-up period in this trial was 12 months. Intratumoral injections of Hsp70 were well tolerated by patients. One patient had a complete clinical response documented by radiologic findings and one patient had a partial response. A positive delayed-type hypersensitivity test was observed in three patients. In peripheral blood, there was a shift from cytokines provided by Th2 cells toward cytokines of a Th1-cell-mediated response. These data corresponded to changes in lymphocyte subpopulations. Immunosuppressive T-regulatory cell levels were also reduced after injection of Hsp70, as well as production of interleukin-10. The cytolytic activity of natural killer cells was unchanged. The present study demonstrates the feasibility of intratumoral delivery

  11. Limited Role for Biliary Stent as Surrogate Fiducial Marker in Pancreatic Cancer: Stent and Intratumoral Fiducials Compared

    Energy Technology Data Exchange (ETDEWEB)

    Horst, Astrid van der, E-mail: a.vanderhorst@amc.uva.nl [Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Amsterdam (Netherlands); Lens, Eelco; Wognum, Silvia; Jong, Rianne de [Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Amsterdam (Netherlands); Hooft, Jeanin E. van [Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam (Netherlands); Tienhoven, Geertjan van; Bel, Arjan [Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Amsterdam (Netherlands)

    2014-07-01

    Purpose: Because of low soft-tissue contrast of cone beam computed tomography (CBCT), fiducial markers are often used for radiation therapy patient setup verification. For pancreatic cancer patients, biliary stents have been suggested as surrogate fiducials. Using intratumoral fiducials as standard for tumor position, this study aims to quantify the suitability of biliary stents for measuring interfractional and respiratory-induced position variations of pancreatic tumors. Methods and Materials: Eleven pancreatic cancer patients with intratumoral fiducials and a biliary stent were included in this study. Daily CBCT scans (243 in total) were registered with a reference CT scan, based on bony anatomy, on fiducial markers, and on the biliary stent, respectively. We analyzed the differences in tumor position (ie, markers center-of-mass position) among these 3 registrations. In addition, we measured for 9 patients the magnitude of respiratory-induced motion (MM) of the markers and of the stent on 4-dimensional CT (4DCT) and determined the difference between these 2 magnitudes (ΔMM). Results: The stent indicated tumor position better than bony anatomy in 67% of fractions; the absolute difference between the markers and stent registration was >5 mm in 46% of fractions and >10 mm in 20% of fractions. Large PTV margins (superior-inferior direction, >19 mm) would be needed to account for this interfractional position variability. On 4DCT, we found in superior-inferior direction a mean ΔMM of 0.5 mm (range, –2.6 to 4.2 mm). Conclusions: For respiratory-induced motion, the mean ΔMM is small, but for individual patients the absolute difference can be >4 mm. For interfractional position variations, a stent is, on average, a better surrogate fiducial than bony anatomy, but large PTV margins would still be required. Therefore, intratumoral fiducials are recommended for online setup verification for all pancreatic patients scheduled for radiation therapy, including

  12. Quantitative image analysis of intra-tumoral bFGF level as a molecular marker of paclitaxel resistance

    Directory of Open Access Journals (Sweden)

    Wientjes M Guillaume

    2008-01-01

    Full Text Available Abstract Background The role of basic fibroblast growth factor (bFGF in chemoresistance is controversial; some studies showed a relationship between higher bFGF level and chemoresistance while other studies showed the opposite finding. The goal of the present study was to quantify bFGF levels in archived tumor tissues, and to determine its relationship with chemosensitivity. Methods We established an image analysis-based method to quantify and convert the immunostaining intensity of intra-tumor bFGF to concentrations; this was accomplished by generating standard curves using human xenograft tumors as the renewable tissue source for simultaneous image analysis and ELISA. The relationships between bFGF concentrations and tumor chemosensitivity of patient tumors (n = 87 to paclitaxel were evaluated using linear regression analysis. Results The image analysis results were compared to our previous results obtained using a conventional, semi-quantitative visual scoring method. While both analyses indicated an inverse relationship between bFGF level and tumor sensitivity to paclitaxel, the image analysis method, by providing bFGF levels in individual tumors and therefore more data points (87 numerical values as opposed to four groups of staining intensities, further enabled the quantitative analysis of the relationship in subgroups of tumors with different pathobiological properties. The results show significant correlation between bFGF level and tumor sensitivity to the antiproliferation effect, but not the apoptotic effect, of paclitaxel. We further found stronger correlations of bFGF level and paclitaxel sensitivity in four tumor subgroups (high stage, positive p53 staining, negative aFGF staining, containing higher-than-median bFGF level, compared to all other groups. These findings suggest that the relationship between intra-tumoral bFGF level and paclitaxel sensitivity was context-dependent, which may explain the previous contradictory findings

  13. A histological evaluation and in vivo assessment of intratumoral near infrared photothermal nanotherapy-induced tumor regression

    Directory of Open Access Journals (Sweden)

    Green HN

    2014-11-01

    Full Text Available Hadiyah N Green,1,2 Stephanie D Crockett,3 Dmitry V Martyshkin,1 Karan P Singh,2,4 William E Grizzle,2,5 Eben L Rosenthal,2,6 Sergey B Mirov11Department of Physics, Center for Optical Sensors and Spectroscopies, 2Comprehensive Cancer Center, 3Department of Pediatrics, Division of Neonatology, 4Department of Medicine, Division of Preventive Medicine, Biostatistics and Bioinformatics Shared Facility, 5Department of Pathology, 6Department of Surgery, Division of Otolaryngology, Head and Neck Surgery, The University of Alabama at Birmingham, Birmingham, AL, USAPurpose: Nanoparticle (NP-enabled near infrared (NIR photothermal therapy has realized limited success in in vivo studies as a potential localized cancer therapy. This is primarily due to a lack of successful methods that can prevent NP uptake by the reticuloendothelial system, especially the liver and kidney, and deliver sufficient quantities of intravenously injected NPs to the tumor site. Histological evaluation of photothermal therapy-induced tumor regression is also neglected in the current literature. This report demonstrates and histologically evaluates the in vivo potential of NIR photothermal therapy by circumventing the challenges of intravenous NP delivery and tumor targeting found in other photothermal therapy studies.Methods: Subcutaneous Cal 27 squamous cell carcinoma xenografts received photothermal nanotherapy treatments, radial injections of polyethylene glycol (PEG-ylated gold nanorods and one NIR 785 nm laser irradiation for 10 minutes at 9.5 W/cm2. Tumor response was measured for 10–15 days, gross changes in tumor size were evaluated, and the remaining tumors or scar tissues were excised and histologically analyzed.Results: The single treatment of intratumoral nanorod injections followed by a 10 minute NIR laser treatment also known as photothermal nanotherapy, resulted in ~100% tumor regression in ~90% of treated tumors, which was statistically significant in a

  14. Anti-inflammatory drugs suppress proliferation and induce apoptosis through altering expressions of cell cycle regulators and pro-apoptotic factors in cultured human osteoblasts

    International Nuclear Information System (INIS)

    It has been reported that anti-inflammatory drugs (AIDs) inhibited bone repair in animal studies, and suppressed proliferation and induced cell death in rat osteoblast cultures. In this study, we further investigated the molecular mechanisms of AID effects on proliferation and cell death in human osteoblasts (hOBs). We examined the effects of dexamethasone (10-7 and 10-6 M), non-selective non-steroidal anti-inflammatory drugs (NSAIDs): indomethacin, ketorolac, piroxicam and diclofenac (10-5 and 10-4 M), and COX-2 inhibitor: celecoxib (10-6 and 10-5 M) on proliferation, cytotoxicity, cell death, and mRNA and protein levels of cell cycle and apoptosis-related regulators in hOBs. All the tested AIDs significantly inhibited proliferation and arrested cell cycle at G0/G1 phase in hOBs. Celecoxib and dexamethasone, but not non-selective NSAIDs, were found to have cytotoxic effects on hOB, and further demonstrated to induce apoptosis and necrosis (at higher concentration) in hOBs. We further found that indomethacin, celecoxib and dexamethasone increased the mRNA and protein expressions of p27kip1 and decreased those of cyclin D2 and p-cdk2 in hOBs. Bak expression was increased by celecoxib and dexamethasone, while Bcl-XL level was declined only by dexamethasone. Furthermore, the replenishment of PGE1, PGE2 or PGF2α did not reverse the effects of AIDs on proliferation and expressions of p27kip1 and cyclin D2 in hOBs. We conclude that the changes in expressions of regulators of cell cycle (p27kip1 and cyclin D2) and/or apoptosis (Bak and Bcl-XL) by AIDs may contribute to AIDs caused proliferation suppression and apoptosis in hOBs. This effect might not relate to the blockage of prostaglandin synthesis by AIDs

  15. Pharmacological modulation of lateral habenular dopamine D2 receptors alters the anxiogenic response to cocaine in a runway model of drug self-administration.

    Science.gov (United States)

    Shelton, Kerisa; Bogyo, Kelsie; Schick, Tinisha; Ettenberg, Aaron

    2016-09-01

    Cocaine has long been known to produce an initial "high" followed by an aversive/anxiogenic "crash". While much is known about the neurobiology of cocaine's positive/rewarding effects, the mechanisms that give rise to the drug's negative/anxiogenic actions remain unclear. Recent research has implicated the lateral habenula (LHb) in the encoding of aversive events including the anxiogenic response to cocaine. Of particular interest in this regard are the reciprocal connections between the LHb and the ventral tegmental area (VTA). VTA-DA neurons innervate different subsets of LHb cells that in turn feedback upon and modulate VTA neuronal activity. Here we examined the impact of D2 receptor activation and inhibition on the anxiogenic response to cocaine using a runway model of self-administration that is sensitive to the dual and opposing effects of the drug. Male rats ran a straight alley for IV cocaine (1.0mg/kg) following bilateral intra-LHb infusions of the D2 receptor antagonist, cis-flupenthixol (0, 7.5 or 15μg/side) or the D2 agonist, sumanirole (0, 5 or 10μg/side). Vehicle-pretreated controls developed approach-avoidance conflict behaviors about goal-box entry reflective of the dual positive and negative effects of cocaine. These behaviors were significantly diminished during LHb-D2 receptor antagonism and increased by the LHb D2 receptor agonist. These results demonstrate that activity at the D2 receptor in the lateral habenula serves to modulate the anxiogenic response to cocaine. PMID:27155504

  16. Assessing intratumor heterogeneity and tracking longitudinal and spatial clonal evolutionary history by next-generation sequencing.

    Science.gov (United States)

    Jiang, Yuchao; Qiu, Yu; Minn, Andy J; Zhang, Nancy R

    2016-09-13

    Cancer is a disease driven by evolutionary selection on somatic genetic and epigenetic alterations. Here, we propose Canopy, a method for inferring the evolutionary phylogeny of a tumor using both somatic copy number alterations and single-nucleotide alterations from one or more samples derived from a single patient. Canopy is applied to bulk sequencing datasets of both longitudinal and spatial experimental designs and to a transplantable metastasis model derived from human cancer cell line MDA-MB-231. Canopy successfully identifies cell populations and infers phylogenies that are in concordance with existing knowledge and ground truth. Through simulations, we explore the effects of key parameters on deconvolution accuracy and compare against existing methods. Canopy is an open-source R package available at https://cran.r-project.org/web/packages/Canopy/. PMID:27573852

  17. Therapeutic effect of intratumoral injection of 188Re labeled stannic sulfur suspension in liver cancer. A comparative study with chemical agents in nude mice

    International Nuclear Information System (INIS)

    Objectives: Hepatoma is a common disease in some countries. The intervention therapy was used often for non-resectable tumor. The aim of our study was to compare the therapeutic effect of 188Re labeled stannic sulfur suspension to ethanol, acetic acid and the mixture of mitomycin and lipiodol for hepatoma in an animal model by intermittently injection. Methods: Forty-nine nude mice bearing hepatic cell carcinoma were divided into six groups. Group 1 (n=14) was intratumoral y injected with 0.1 ml saline. There were 5 experimental groups (group 2 to 6). Each group consisted of 7 mice. The mice in group 2 was intratumoral y injected with 18.5 MBq/0.1 ml 188Re labeled stannic sulfur suspension each, the mice in group 3 was injected intratumorally with 9.25 MBq/0.1 ml 188Re labeled stannic sulfur suspension each, group 4 was injected intratumorally with 0.1 ml ethanol, the mice in group 5 was injected with 0.1 ml 30% acetic acid and group 6 was injected intratumorally with 30 μg mitomycin in 0.1 ml lipiodol respectively. The mice were sacrificed 7 days post injection and the specimen were collected for pathological analysis. Results: The average tumor weight were 1.75±0.29 g (mean±S.D.), 0.26±0.03 g, 0.44±0.17 g, 1.38±0.25 g, 0.91±0.28 g, 1.38±0.28 g for group 1 to 6 respectively. Tumors in all experimental groups were significantly smaller than group 1 (control group, P88Re labeled stannic sulfur suspension injection had the smallest tumor weight among all the experimental groups (P188Re labeled stannic sulfur suspension shows better therapeutic effect. (authors)

  18. Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors.

    Science.gov (United States)

    Cai, Changmeng; Chen, Sen; Ng, Patrick; Bubley, Glenn J; Nelson, Peter S; Mostaghel, Elahe A; Marck, Brett; Matsumoto, Alvin M; Simon, Nicholas I; Wang, Hongyun; Chen, Shaoyong; Balk, Steven P

    2011-10-15

    Relapse of castration-resistant prostate cancer (CRPC) that occurs after androgen deprivation therapy of primary prostate cancer can be mediated by reactivation of the androgen receptor (AR). One important mechanism mediating this AR reactivation is intratumoral conversion of the weak adrenal androgens DHEA and androstenedione into the AR ligands testosterone and dihydrotestosterone. DHEA and androstenedione are synthesized by the adrenals through the sequential actions of the cytochrome P450 enzymes CYP11A1 and CYP17A1, so that CYP17A1 inhibitors such as abiraterone are effective therapies for CRPC. However, the significance of intratumoral CYP17A1 and de novo androgen synthesis from cholesterol in CRPC, and the mechanisms contributing to CYP17A1 inhibitor resistance/relapse, remain to be determined. We report that AR activity in castration-resistant VCaP tumor xenografts can be restored through CYP17A1-dependent de novo androgen synthesis, and that abiraterone treatment of these xenografts imposes selective pressure for increased intratumoral expression of CYP17A1, thereby generating a mechanism for development of resistance to CYP17A1 inhibitors. Supporting the clinical relevance of this mechanism, we found that intratumoral expression of CYP17A1 was markedly increased in tumor biopsies from CRPC patients after CYP17A1 inhibitor therapy. We further show that CRPC cells expressing a progesterone responsive T877A mutant AR are not CYP17A1 dependent, but that AR activity in these cells is still steroid dependent and mediated by upstream CYP11A1-dependent intraturmoral pregnenolone/progesterone synthesis. Together, our results indicate that CRPCs resistant to CYP17A1 inhibition may remain steroid dependent and therefore responsive to therapies that can further suppress de novo intratumoral steroid synthesis.

  19. Increased intratumoral FOXP3-positive regulatory immune cells during interleukin-2 treatment in metastatic renal cell carcinoma

    DEFF Research Database (Denmark)

    Jensen, Hanne Krogh; Donskov, Frede; Nordsmark, Marianne;

    2009-01-01

    tumor-infiltrating immune cells at baseline and during treatment (P 180 cells/mm2) of on-treatment FOXP3-positive intratumoral immune cells were dead within 22 months (n = 11), whereas patients with low numbers (cells/mm2) of on-treatment......PURPOSE: The administration of interleukin-2 (IL-2) may increase the frequency of peripherally circulating FOXP3-positive regulatory immune cells, thus potentially compromising this treatment option for patients with metastatic renal cell carcinoma. The impact of IL-2-based therapy...... on the accumulation of FOXP3-positive immune cells in the tumor microenvironment in metastatic renal cell carcinoma is unknown. EXPERIMENTAL DESIGN: Baseline (n = 58) and on-treatment (n = 42) tumor core biopsies were prospectively obtained from patients with clear cell metastatic renal cell carcinoma before...

  20. ROLE OF THE MORPHOMETRIC PARAMETERS OF INTRATUMORAL MICROVESSELS AND THE PROLIFERATIVE ACTIVITY OF TUMOR CELLS IN RENAL CELL CARCINOMA

    Directory of Open Access Journals (Sweden)

    N. A. Gorban

    2014-08-01

    Full Text Available Tumor cell proliferation and angiogenesis are essential factors for tumor growth, progression, and metastasis.Objective: to assess the relationship between the values of proliferative activity and the morphometric parameters of intratumoral microvessels in metastatic and localized carcinomas of the kidney.Materials and methods. Surgical specimens taken from 54 patients (32 men and 22 women aged 26 to 69 years (mean age 55 ± 1.5 years with the verified diagnosis of clear-cell renal cell carcinoma (RCC were studied.Conclusion. Proliferative activity and angioarchitectonics are an important biological characteristic of a tumor of unequal clinical value in RCC. Metastatic carcinoma has a higher proliferative activity and a low tumor vascularization than those of localized carcinoma.

  1. Increased Survivorship and Altered Cytokine Profile from Treatment of Influenza A H1N1-Infected Mice with Ekybion: A Drug Complex of Natural Extracts and Inorganic Compounds

    Directory of Open Access Journals (Sweden)

    Christopher Lupfer

    2011-01-01

    Full Text Available Ekybion is a drug complex of 16 natural extracts and inorganic compounds designed to treat a variety of respiratory pathogens of bacterial and viral origin. It is licensed throughout Europe for the treatment of respiratory tract infections from equine parainfluenza type 3 and equine herpes virus type 1 in equine stables. The purpose of this paper was to test the efficacy of Ekybion on a well-developed animal model of influenza A infection and determine a mode of action. Experiments were performed with Balb/c mice infected with a lethal dose of influenza A/PR/8/34 H1N1 virus and treated with nebulized Ekybion every 8 h in a time-dependant or dose-dependant fashion. These experiments showed that mice treated prior to infection with Ekybion had a higher survival rates (~46% compared with untreated animals (~0%. Paradoxically, these mice showed no significant difference in lung virus titer or weight loss. There was, however, a decrease in the level of GM-CSF, IL-6, and G-CSF cytokines in the lungs of Ekybion-treated, infected mice. It is possible that decreases in proinflammatory cytokines may have contributed to increased survivorship in Ekybion-treated influenza-infected mice.

  2. Alteration of basal ganglia and right frontoparietal network in early drug-naïve Parkinson’s disease during heat pain stimuli and resting state

    Directory of Open Access Journals (Sweden)

    Ying eTan

    2015-08-01

    Full Text Available Background: The symptoms and pathogenesis of Parkinson’s disease (PD are complicated and accurate diagnosis is difficult, particularly in early-stage. Functional magnetic resonance imaging is noninvasive and characterized by the integration of different brain areas at functional connectivity (FC. Considering pain process in PD, we hypothesized that pain is one of the earliest symptoms and investigated whether FC of the pain network was disrupted in PD without pain.Methods: Fourteen early drug-naïve PD without pain and 17 age- and sex-matched healthy controls (HC participated in our test. We investigate abnormalities in FC and in functional network connectivity in PD compared with HC during the task (51 °C heat pain stimuli and at rest.Results: Compared with HC, PD showed decreased FC in basal ganglia network (BGN, salience network (SN and sensorimotor network in two states respectively. FNC between the BGN and the SN are reduced during both states in PD compared with HC. In addition, the FNC associated with right frontoparietal network (RFPN was also significantly disturbed during the task.Conclusion: These findings suggest that BGN plays a role in the pathological mechanisms of pain underlying PD, and RFPN likely contributes greatly to harmonization between intrinsic brain activity and external stimuli.

  3. Antiretroviral drugs.

    Science.gov (United States)

    De Clercq, Erik

    2010-10-01

    In October 2010, it will be exactly 25 years ago that the first antiretroviral drug, AZT (zidovudine, 3'-azido-2',3'-dideoxythymidine), was described. It was the first of 25 antiretroviral drugs that in the past 25 years have been formally licensed for clinical use. These antiretroviral drugs fall into seven categories [nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors (FIs), co-receptor inhibitors (CRIs) and integrase inhibitors (INIs). The INIs (i.e. raltegravir) represent the most recent advance in the search for effective and selective anti-HIV agents. Combination of several anti-HIV drugs [often referred to as highly active antiretroviral therapy (HAART)] has drastically altered AIDS from an almost uniformly fatal disease to a chronic manageable one. PMID:20471318

  4. Antiretroviral drugs.

    Science.gov (United States)

    De Clercq, Erik

    2010-10-01

    In October 2010, it will be exactly 25 years ago that the first antiretroviral drug, AZT (zidovudine, 3'-azido-2',3'-dideoxythymidine), was described. It was the first of 25 antiretroviral drugs that in the past 25 years have been formally licensed for clinical use. These antiretroviral drugs fall into seven categories [nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors (FIs), co-receptor inhibitors (CRIs) and integrase inhibitors (INIs). The INIs (i.e. raltegravir) represent the most recent advance in the search for effective and selective anti-HIV agents. Combination of several anti-HIV drugs [often referred to as highly active antiretroviral therapy (HAART)] has drastically altered AIDS from an almost uniformly fatal disease to a chronic manageable one.

  5. Does thyroidectomy, radioactive iodine therapy, or antithyroid drug treatment alter reactivity of patients` T cells to epitopes of thyrotropin receptor in autoimmune thyroid diseases?

    Energy Technology Data Exchange (ETDEWEB)

    Soliman, M.; Kaplan, E.; Abdel-Latif, A. [Univ. of Chicago, IL (United States)] [and others

    1995-08-01

    The effect of treatment on thyroid antibody production and T cell reactivity to thyroid antigens was studied in 15 patients with Graves` disease (GD) before and after thyroidectomy, 19 patients with GD before and after radioactive iodine (RAI) therapy, and 9 patients maintained euthyroid on antithyroid drugs (ATD). In GD patients, the responses of peripheral blood mononuclear cells (PBMC) and TSH receptor (TSHR)-specific T cell lines to recombinant human TSHR extracellular domain, thyroglobulin, and TSHR peptides were examined on the day of surgery or RAI therapy (day 0) and also 6-8 weeks and 3-6 months thereafter. Reactivity to TSHR peptides before surgery was heterogeneous and spanned the entire extracellular domain. Six to 8 weeks after subtotal thyroidectomy, the number of patients` PBMC responding to any peptide and the average number of recognized peptides decreased. A further decrease in the T cell reactivity to TSHR peptides was observed 3-6 months after surgery. The responses of PBMC from Graves` patients before RAI therapy were less than those in the presurgical group. Six to 8 weeks after RAI therapy, the number of patients responding to any peptide and the average number of recognized peptides increased. Three to 6 months after RAI, T cell responses to TSHR peptides were less than those 6-8 weeks after RAI therapy, but still higher than the values on day 0. Responses of PBMC from patients with GD, maintained euthyroid on ATD, were lower than those before surgery or RAI therapy. The reactivity of T cell lines in different groups reflected a pattern similar to PBMC after treatment. TSHR antibody and microsomal antibody levels decreased after surgery, but increased after RAI therapy. The difference in the number of recognized peptides by patients` PBMC before RAI and surgery may reflect the effect of long term therapy with ATD in the patients before RAI vs. the shorter period in patients before surgery. 38 refs., 2 figs., 5 tabs.

  6. Does thyroidectomy, radioactive iodine therapy, or antithyroid drug treatment alter reactivity of patients' T cells to epitopes of thyrotropin receptor in autoimmune thyroid diseases?

    International Nuclear Information System (INIS)

    The effect of treatment on thyroid antibody production and T cell reactivity to thyroid antigens was studied in 15 patients with Graves' disease (GD) before and after thyroidectomy, 19 patients with GD before and after radioactive iodine (RAI) therapy, and 9 patients maintained euthyroid on antithyroid drugs (ATD). In GD patients, the responses of peripheral blood mononuclear cells (PBMC) and TSH receptor (TSHR)-specific T cell lines to recombinant human TSHR extracellular domain, thyroglobulin, and TSHR peptides were examined on the day of surgery or RAI therapy (day 0) and also 6-8 weeks and 3-6 months thereafter. Reactivity to TSHR peptides before surgery was heterogeneous and spanned the entire extracellular domain. Six to 8 weeks after subtotal thyroidectomy, the number of patients' PBMC responding to any peptide and the average number of recognized peptides decreased. A further decrease in the T cell reactivity to TSHR peptides was observed 3-6 months after surgery. The responses of PBMC from Graves' patients before RAI therapy were less than those in the presurgical group. Six to 8 weeks after RAI therapy, the number of patients responding to any peptide and the average number of recognized peptides increased. Three to 6 months after RAI, T cell responses to TSHR peptides were less than those 6-8 weeks after RAI therapy, but still higher than the values on day 0. Responses of PBMC from patients with GD, maintained euthyroid on ATD, were lower than those before surgery or RAI therapy. The reactivity of T cell lines in different groups reflected a pattern similar to PBMC after treatment. TSHR antibody and microsomal antibody levels decreased after surgery, but increased after RAI therapy. The difference in the number of recognized peptides by patients' PBMC before RAI and surgery may reflect the effect of long term therapy with ATD in the patients before RAI vs. the shorter period in patients before surgery. 38 refs., 2 figs., 5 tabs

  7. Nanoparticles for Targeting Intratumoral Hypoxia: Exploiting a Potential Weakness of Glioblastoma.

    Science.gov (United States)

    Aldea, Mihaela; Florian, Ioan Alexandru; Kacso, Gabriel; Craciun, Lucian; Boca, Sanda; Soritau, Olga; Florian, Ioan Stefan

    2016-09-01

    Extensive hypoxic regions are the daunting hallmark of glioblastoma, as they host aggressive stem-like cells, hinder drug delivery and shield cancer cells from the effects of radiotherapy. Nanotechnology could address most of these issues, as it employs nanoparticles (NPs) carrying drugs that selectively accumulate and achieve controlled drug release in tumor tissues. Methods overcoming the stiff interstitium and scarce vascularity within hypoxic zones include the incorporation of collagenases to degrade the collagen-rich tumor extracellular matrix, the use of multistage systems that progressively reduce NP size or of NP-loaded cells that display inherent hypoxia-targeting abilities. The unfavorable hypoxia-induced low pH could be converted into a therapeutical advantage by pH-responsive NPs or multilayer NPs, while overexpressed markers of hypoxic cells could be specifically targeted for an enhanced preferential drug delivery. Finally, promising new gene therapeutics could also be incorporated into nanovehicles, which could lead to silencing of hypoxia-specific genes that are overexpressed in cancer cells. In this review, we highlight NPs which have shown promising results in targeting cancer hypoxia and we discuss their applicability in glioblastoma, as well as possible limitations. Novel research directions in this field are also considered. PMID:27230936

  8. Preclinical examination of clofarabine in pediatric ependymoma: Intratumoral concentrations insufficient to warrant further study

    OpenAIRE

    Patel, Yogesh T.; Jacus, Megan O.; Boulos, Nidal; Dapper, Jason D.; Davis, Abigail D.; Vuppala, Pradeep K.; Freeman, Burgess B.; Mohankumar, Kumarasamypet M.; Throm, Stacy L.; Gilbertson, Richard J.; Stewart, Clinton F.

    2015-01-01

    Clofarabine, a deoxyadenosine analog, was an active anticancer drug in our in vitro high-throughput screening against mouse ependymoma neurospheres. To characterize the clofarabine disposition in mice for further preclinical efficacy studies, we evaluated the plasma and central nervous system (CNS) disposition in a mouse model of ependymoma. A plasma pharmacokinetic study of clofarabine (45 mg/kg, IP) was performed in CD1 nude mice bearing ependymoma to obtain initial plasma pharmacokinetic p...

  9. Longitudinal immune monitoring of patients receiving intratumoral injection of a MART-1 T-cell receptor-transduced cell line (C-Cure 709)

    DEFF Research Database (Denmark)

    Køllgaard, Tania; Duval, Lone; Schmidt, Henrik;

    2009-01-01

    BACKGROUND AIMS: Adoptive transfer of tumor-specific lymphocytes is a promising strategy in the treatment of cancer. We conducted intratumoral administration of an allogeneic irradiated continuous T-cell line (C-Cure 709) expressing an HLA-A2-restricted MART-1-specific T-cell receptor (TCR......) into HLA-A2(+) melanoma patients. The C-Cure 709 cell line is cytotoxic against MART-1(+) HLA-A2(+) melanoma cell lines and secretes several immune stimulatory cytokines upon stimulation. METHODS: Anti-tumor immune responses against the commonly expressed tumor antigen (Ag) MART-1 were longitudinally...... analyzed in peripheral blood by fluorescence-activated cell sorting (FACS) before and after intratumoral injection of C-Cure 709. RESULTS: No treatment-induced increase in Ag-specific T-cell frequencies was observed in peripheral blood, and the phenotype of MART-1-specific T cells was very stable during...

  10. Intratumoral delivery of encapsulated IL-12, IL-18 and TNF-alpha in a model of metastatic breast cancer.

    Science.gov (United States)

    Sabel, Michael S; Su, Gang; Griffith, Kent A; Chang, Alfred E

    2010-07-01

    Intratumoral (i.t.) cytokine release through the use of poly-lactic acid microspheres (PLAM) holds tremendous potential for the immunotherapy of breast cancer as it harnesses the immunologic potential of autologous tumor in a clinically feasible and minimally toxic manner. We examined the potential of combinations of i.t. IL-12, IL-18 and TNF-alpha PLAM to generate a tumor-specific immune response and improve outcome in a model of metastatic breast cancer. Balb/c mice with established 4T1 mammary carcinomas were treated with a single injection of BSA, IL-12, IL-18 or TNF-alpha-loaded PLAM alone or in combination after spontaneous metastases occurred. Combined treatment with IL-12 and TNF-alpha PLAM was superior to all other treatments, including the triple combination of IL-12, IL-18 and TNF-alpha in ablation of the primary tumor, eradicating distant disease and enhancing survival. Simultaneous delivery of IL-12 and TNF-alpha was superior to sequential delivery of IL-12 followed by TNF-alpha, but not TNF-alpha followed by IL-12. In vivo lymphocyte depletion studies established that the effects of IL-12 alone are mediated primarily by NK cells, while the combination of IL-12 and TNF-alpha is dependent upon CD8+ T-cells. Only the combination of IL-12 and TNF-alpha results in an increase in both CD4+ and CD8+ T-cells and a reduction in CD4+CD25+ cells. While there was no change in the dendritic cell population, IL-12 and TNF-alpha resulted in a dramatic increase in DC maturation and antigen presentation. Neoadjuvant immunotherapy with simultaneous intratumoral delivery of IL-12 and TNF-alpha PLAM augments DC antigen presentation and increases cytotoxic T-cells without increasing regulatory T-cells, resulting in a T-cell based anti-tumor immune response capable of eradicating disseminated disease. The addition of IL-18 did not improve the efficacy. PMID:19802695

  11. Evaluating dynamic contrast-enhanced and photoacoustic CT to assess intra-tumor heterogeneity in xenograft mouse models

    Science.gov (United States)

    Stantz, Keith M.; Liu, Bo; Cao, Minsong; Reinecke, Dan; Dzemidzic, Mario; Liang, Yun; Kruger, Robert

    2006-03-01

    Purpose: To evaluate photoacoustic CT spectroscopy (PCT-S) and dynamic contrast-enhanced CT (DCE-CT) ability to measure parameters - oxygen saturation and vascular physiology - associated with the intra-tumor oxygenation status. Material and Methods: Breast (VEGF165 enhance MCF-7) and ovarian (SKOV3x) cancer cells were implanted into the fat pads and flanks of immune deficient mice and allowed to grow to a diameter of 8-15 mm. CT was used to determine physiological parameters by acquiring a sequence of scans over a 10 minute period after an i.v. injection of a radio-opaque contrast agent (Isovue). These time-dependent contrast-enhanced curves were fit to a two-compartmental model determining tumor perfusion, fractional plasma volume, permeability-surface area produce, and fractional interstitial volume on a voxel-by-voxel basis. After which, the tumors were imaged using photoacoustic CT (Optosonics, Inc., Indianapolis, IN 46202). The near infrared spectra (700-910 nm) within the vasculature was fit to linear combination of measured oxy- and deoxy-hemoglobin blood samples to obtain oxygen saturation levels (SaO II). Results: The PCT-S scanner was first calibrated using different samples of oxygenated blood, from which a statistical error ranging from 2.5-6.5% was measured and a plot of the hemoglobin dissociation curve was consistent with empirical formula. In vivo determination of tumor vasculature SaO II levels were measurably tracked, and spatially correlated to the periphery of the tumor. Tumor depend variations in SaO II - 0.32 (ovarian) and 0.60 (breast) - and in vascular physiology - perfusion, 1.03 and 0.063 mL/min/mL, and fractional plasma volume, 0.20 and 0.07 - were observed. Conclusion: Combined, PCT-S and CED-CT has the potential to measure intra-tumor levels of tumor oxygen saturation and vascular physiology, key parameters associated with hypoxia.

  12. Smectite alteration

    International Nuclear Information System (INIS)

    This report contains the proceedings of a second workshop in Washington DC December 8-9, 1983 on the alteration of smectites intended for use as buffer materials in the long-term containment of nuclear wastes. It includes extended summaries of all presentations and a transcript of the detailed scientific discussion. The discussions centered on three main questions: What is the prerequisite for and what is the precise mechanism by which smectite clays may be altered to illite. What are likly sources of potassium with respect to the KBS project. Is it likely that the conversion of smectite to illite will be of importance in the 10 5 to the 10 6 year time frame. The workshop was convened to review considerations and conclusions in connection to these questions and also to broaden the discussion to consider the use of smectite clays as buffer materials for similar applications in different geographical and geological settings. SKBF/KBS technical report 83-03 contains the proceedings from the first workshop on these matters that was held at the State University of New York, Buffalo May 26-27, 1982. (Author)

  13. Phase I study to evaluate toxicity and feasibility of intratumoral injection of α-gal glycolipids in patients with advanced melanoma.

    Science.gov (United States)

    Albertini, Mark R; Ranheim, Erik A; Zuleger, Cindy L; Sondel, Paul M; Hank, Jacquelyn A; Bridges, Alan; Newton, Michael A; McFarland, Thomas; Collins, Jennifer; Clements, Erin; Henry, Mary Beth; Neuman, Heather B; Weber, Sharon; Whalen, Giles; Galili, Uri

    2016-08-01

    Effective uptake of tumor cell-derived antigens by antigen-presenting cells is achieved pre-clinically by in situ labeling of tumor with α-gal glycolipids that bind the naturally occurring anti-Gal antibody. We evaluated toxicity and feasibility of intratumoral injections of α-gal glycolipids as an autologous tumor antigen-targeted immunotherapy in melanoma patients (pts). Pts with unresectable metastatic melanoma, at least one cutaneous, subcutaneous, or palpable lymph node metastasis, and serum anti-Gal titer ≥1:50 were eligible for two intratumoral α-gal glycolipid injections given 4 weeks apart (cohort I: 0.1 mg/injection; cohort II: 1.0 mg/injection; cohort III: 10 mg/injection). Monitoring included blood for clinical, autoimmune, and immunological analyses and core tumor biopsies. Treatment outcome was determined 8 weeks after the first α-gal glycolipid injection. Nine pts received two intratumoral injections of α-gal glycolipids (3 pts/cohort). Injection-site toxicity was mild, and no systemic toxicity or autoimmunity could be attributed to the therapy. Two pts had stable disease by RECIST lasting 8 and 7 months. Tumor nodule biopsies revealed minimal to no change in inflammatory infiltrate between pre- and post-treatment biopsies except for 1 pt (cohort III) with a post-treatment inflammatory infiltrate. Two and four weeks post-injection, treated nodules in 5 of 9 pts exhibited tumor cell necrosis without neutrophilic or lymphocytic inflammatory response. Non-treated tumor nodules in 2 of 4 evaluable pts also showed necrosis. Repeated intratumoral injections of α-gal glycolipids are well tolerated, and tumor necrosis was seen in some tumor nodule biopsies after tumor injection with α-gal glycolipids. PMID:27207605

  14. Prediction of microvascular invasion of hepatocellular carcinomas with gadoxetic acid-enhanced MR imaging: Impact of intra-tumoral fat detected on chemical-shift images

    Energy Technology Data Exchange (ETDEWEB)

    Min, Ji Hye [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Kim, Young Kon, E-mail: jmyr@dreamwiz.com [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Lim, Sanghyeok [Department of Radiology, Guri Hospital, Hanyang University College of Medicine, Guri (Korea, Republic of); Jeong, Woo Kyoung; Choi, Dongil; Lee, Won Jae [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2015-06-15

    Highlights: • Intra-tumoral fat detected with MR imaging may suggest lower risk for MVI of HCC. • Alfa-fetoprotein, tumor size, and fat component were associated with MVI of HCC. • Chemical shift MRI should be considered for the evaluation of HCC. - Abstract: Purpose: To investigate the impact of intra-tumoral fat detected by chemical-shift MR imaging in predicting the MVI of HCC. Materials and methods: Gadoxetic acid-enhanced MR imaging of 365 surgically proven HCCs from 365 patients (306 men, 59 women; mean age, 55.6 years) were evaluated. HCCs were classified into two groups, fat-containing and non-fat-containing, based on the presence of fat on chemical-shift images. Fat-containing HCCs were subdivided into diffuse or focal fatty change groups. Logistic regression analyses were used to identify clinical and MR findings associated with MVI. Results: Based on MR imaging, 66 tumors were classified as fat-containing HCCs and 299 as non-fat-containing HCCs. Among the 66 fat-containing HCCs, 38 (57.6%) showed diffuse fatty changes and 28 (42.4%) showed focal fatty changes. MVI was present in 18 (27.3%) fat-containing HCCs and in 117 (39.1%) non-fat-containing HCCs (P = 0.07). Univariate analysis revealed that serum alpha-fetoprotein (AFP) and tumor size were significantly associated with MVI (P < 0.001). A multiple logistic regression analysis showed that log AFP (odds ratio 1.178, P = 0.0016), tumor size (odds ratio 1.809, P < 0.001), and intra-tumoral fat (odds ratio 0.515, P = 0.0387) were independent variables associated with MVI. Conclusion: Intra-tumoral fat detected with MR imaging may suggest lower risk for MVI of HCC and, therefore, a possibly more favorable prognosis, but the clinical value of this finding is uncertain.

  15. Decreased intratumoral Foxp3 Tregs and increased dendritic cell density by neoadjuvant chemotherapy associated with favorable prognosis in advanced gastric cancer

    OpenAIRE

    Hu, Min; Li, Kai; Maskey, Ninu; Xu, Zhigao; Peng, Chunwei; Wang, Bicheng; Li, Yan; Yang, Guifang

    2014-01-01

    Although neoadjuvant chemotherapy (NACT) has been increasingly used to improve the outcome of advanced gastric cancer (GC) for decades, its precise efficacy has been difficult to evaluate yet. Abundant studies have investigated the predictive factors that represent the effect of NACT on advanced GC. In the present study, the intratumoral infiltration of regulatory T cells (Tregs) and dendritic cells (DCs) response to NACT in advanced GC and their correlation with prognosis were evaluated. Inf...

  16. Phenotypic drug profiling in droplet microfluidics for better targeting of drug-resistant tumors

    Science.gov (United States)

    Sarkar, S.; Cohen, N.; Sabhachandani, P.; Konry, T.

    2015-01-01

    Acquired drug resistance is a key factor in the failure of chemotherapy. Due to intratumoral heterogeneity, cancer cells depict variations in intracellular drug uptake and efflux at the single cell level, which may not be detectable in bulk assays. In this study we present a droplet microfluidics-based approach to assess the dynamics of drug uptake, efflux and cytotoxicity in drug-sensitive and drug-resistant breast cancer cells. An integrated droplet generation and docking microarray was utilized to encapsulate single cells as well as homotypic cell aggregates. Drug-sensitive cells showed greater death in the presence or absence of Doxorubicin (Dox) compared to the drug-resistant cells. We observed heterogeneous Dox uptake in individual drug-sensitive cells while the drug-resistant cells showed uniformly low uptake and retention. Dox-resistant cells were classified into distinct subsets based on their efflux properties. Cells that showed longer retention of extracellular reagents also demonstrated maximal death. We further observed homotypic fusion of both cell types in droplets, which resulted in increased cell survival in the presence of high doses of Dox. Our results establish the applicability of this microfluidic platform for quantitative drug screening in single cells and multicellular interactions. PMID:26456240

  17. Antiangiogenic therapy using endostatin increases the number of ALDH+ lung cancer stem cells by generating intratumor hypoxia

    Science.gov (United States)

    Yu, Yang; Wang, Yu-yi; Wang, Yi-qin; Wang, Xia; Liu, Yan-Yang; Wang, Jian-Tao; Du, Chi; Wang, Li; Li, Mei; Luo, Feng; Jiang, Ming

    2016-01-01

    Antiangiogenic therapy is becoming a promising option for cancer treatment. However, many investigations have recently indicated that these therapies may have limited efficacy, and the cancers in most patients eventually develop resistance to these therapies. There is considerable recently acquired evidence for an association of such resistance with cancer stem-like cells (CSLCs). Here, we used xenograft tumor murine models to further suggest that antiangiogenic agents actually increase the invasive and metastatic properties of lung cancer cells. In our experiments with murine lung cancer xenografts, we found that the antiangiogenic agent endostatin increased the population of ALDH+ cells, and did so by generating intratumoral hypoxia in the xenografts. We further showed endostatin to cause an increase in the CSLC population by accelerating the generation of tumor hypoxia and by recruiting TAMs, MDSCs and Treg cells, which are inflammatory and immunosuppressive cells and which can secrete cytokines and growth factors such as IL-6, EGF, and TGF-β into the tumor microenvironment. All these factors are related with increased CSLC population in tumors. These results imply that improving the clinical efficacy of antiangiogenic treatments will require the concurrent use of CSLC-targeting agents. PMID:27703219

  18. Preclinical examination of clofarabine in pediatric ependymoma: intratumoral concentrations insufficient to warrant further study.

    Science.gov (United States)

    Patel, Yogesh T; Jacus, Megan O; Boulos, Nidal; Dapper, Jason D; Davis, Abigail D; Vuppala, Pradeep K; Freeman, Burgess B; Mohankumar, Kumarasamypet M; Throm, Stacy L; Gilbertson, Richard J; Stewart, Clinton F

    2015-05-01

    Clofarabine, a deoxyadenosine analog, was an active anticancer drug in our in vitro high-throughput screening against mouse ependymoma neurospheres. To characterize the clofarabine disposition in mice for further preclinical efficacy studies, we evaluated the plasma and central nervous system disposition in a mouse model of ependymoma. A plasma pharmacokinetic study of clofarabine (45 mg/kg, IP) was performed in CD1 nude mice bearing ependymoma to obtain initial plasma pharmacokinetic parameters. These estimates were used to derive D-optimal plasma sampling time points for cerebral microdialysis studies. A simulation of clofarabine pharmacokinetics in mice and pediatric patients suggested that a dosage of 30 mg/kg IP in mice would give exposures comparable to that in children at a dosage of 148 mg/m(2). Cerebral microdialysis was performed to study the tumor extracellular fluid (ECF) disposition of clofarabine (30 mg/kg, IP) in the ependymoma cortical allografts. Plasma and tumor ECF concentration-time data were analyzed using a nonlinear mixed effects modeling approach. The median unbound fraction of clofarabine in mouse plasma was 0.79. The unbound tumor to plasma partition coefficient (K pt,uu: ratio of tumor to plasma AUCu,0-inf) of clofarabine was 0.12 ± 0.05. The model-predicted mean tumor ECF clofarabine concentrations were below the in vitro 1-h IC50 (407 ng/mL) for ependymoma neurospheres. Thus, our results show the clofarabine exposure reached in the tumor ECF was below that associated with an antitumor effect in our in vitro washout study. Therefore, clofarabine was de-prioritized as an agent to treat ependymoma, and further preclinical studies were not pursued. PMID:25724157

  19. Darwinian Dynamics of Intratumoral Heterogeneity: Not Solely Random Mutations but Also Variable Environmental Selection Forces.

    Science.gov (United States)

    Lloyd, Mark C; Cunningham, Jessica J; Bui, Marilyn M; Gillies, Robert J; Brown, Joel S; Gatenby, Robert A

    2016-06-01

    Spatial heterogeneity in tumors is generally thought to result from branching clonal evolution driven by random mutations that accumulate during tumor development. However, this concept rests on the implicit assumption that cancer cells never evolve to a fitness maximum because they can always acquire mutations that increase proliferative capacity. In this study, we investigated the validity of this assumption. Using evolutionary game theory, we demonstrate that local cancer cell populations will rapidly converge to the fittest phenotype given a stable environment. In such settings, cellular spatial heterogeneity in a tumor will be largely governed by regional variations in environmental conditions, for example, alterations in blood flow. Model simulations specifically predict a common spatial pattern in which cancer cells at the tumor-host interface exhibit invasion-promoting, rapidly proliferating phenotypic properties, whereas cells in the tumor core maximize their population density by promoting supportive tissue infrastructures, for example, to promote angiogenesis. We tested model predictions through detailed quantitative image analysis of phenotypic spatial distribution in histologic sections of 10 patients with stage 2 invasive breast cancers. CAIX, GLUT1, and Ki67 were upregulated in the tumor edge, consistent with an acid-producing invasive, proliferative phenotype. Cells in the tumor core were 20% denser than the edge, exhibiting upregulation of CAXII, HIF-1α, and cleaved caspase-3, consistent with a more static and less proliferative phenotype. Similarly, vascularity was consistently lower in the tumor center compared with the tumor edges. Lymphocytic immune responses to tumor antigens also trended to higher level in the tumor edge, although this effect did not reach statistical significance. Like invasive species in nature, cancer cells at the leading edge of the tumor possess a different phenotype from cells in the tumor core. Our results suggest

  20. Clinical nutrition and drug interactions

    OpenAIRE

    Ekincioğlu, Aygin Bayraktar; Demirkan, Kutay

    2013-01-01

    A drug’s plasma level, pharmacological effects or side effects, elimination, physicochemical properties or stability could be changed by interactions of drug-drug or drug-nutrition products in patients who receive enteral or parenteral nutritional support. As a result, patients might experience ineffective outcomes or unexpected effects of therapy (such as drug toxicity, embolism). Stability or incompatibility problems between parenteral nutrition admixtures and drugs might lead to alteration...

  1. Transporter-Mediated Drug–Drug Interactions with Oral Antidiabetic Drugs

    OpenAIRE

    Jörg König; Fromm, Martin F; Sabine Klatt

    2011-01-01

    Uptake transporters (e.g., members of the SLC superfamily of solute carriers) and export proteins (e.g., members of the ABC transporter superfamily) are important determinants for the pharmacokinetics of drugs. Alterations of drug transport due to concomitantly administered drugs that interfere with drug transport may alter the kinetics of drug substrates. In vitro and in vivo studies indicate that many drugs used for the treatment of metabolic disorders and cardiovascular diseases (e.g., ora...

  2. Combined Intralesional Neodymium-Doped Yttrium Aluminium Garnet Laser and Intratumoral Ligation as Curative Treatment for Craniofacial Arteriovenous Malformations.

    Science.gov (United States)

    Rojvachiranonda, Nond; Lerdlum, Sukalaya; Mahatumarat, Charan

    2016-03-01

    Craniofacial arteriovenous malformation (AVM), although very rare, has been a very difficult problem to treat especially when it is large and involves important structures. Surgical resection often results in unacceptable complications but still not curative. At our institution, treatment by combined intralesional neodymium-doped yttrium aluminium garnet laser and intratumoral ligation has been successful in venous malformation. This minimally invasive technique was then applied to more challenging AVM on the head and neck. Disease control was studied using clinical parameters and magnetic resonance imaging.Four patients with moderate-to-severe (Schobinger 2-4) craniofacial AVM were treated by this technique from 2001 to 2011. Patient age ranged from 2 to 51 years (mean: 25 years). After 2 to 4 treatments and follow-up period of 1456 days, 3 (75%) were cured. One of them was infant with huge mass and secondary pulmonary hypertension. Clinical cure was achieved after 3 treatments without residual cardiovascular compromise. The other patient (25%) had cheek mass with intraorbital involvement. The authors did not treat periorbital lesion so as to avoid triggering intraorbital spreading. The rest of the cheek lesion was clinically and radiologically cured.Laser energy setting, ablative technique, and skin cooling are the main factors determining the success. Individualized laser settings and properly set endpoints can increase treatment effectiveness in shorter period. In conclusion, this minimally invasive technique was successful in curing AVM without complication. With more clinical study and development of soft tissue monitoring tools, it is possible that intralesional laser could become the treatment of choice for all cutaneous AVM.

  3. Local Control of Lung Derived Tumors by Diffusing Alpha-Emitting Atoms Released From Intratumoral Wires Loaded With Radium-224

    International Nuclear Information System (INIS)

    Purpose: Diffusing alpha-emitters radiation therapy (DART) is a new form of brachytherapy enabling the treatment of solid tumors with alpha radiation. The present study examines the antitumoral effects resulting from the release of alpha emitting radioisotopes into solid lung carcinoma (LL2, A427, and NCI-H520). Methods and Materials: An in vitro setup tested the dose-dependent killing of tumor cells exposed to alpha particles. In in vivo studies, radioactive wires (0.3 mm diameter, 5 mm long) with 224Ra activities in the range of 21-38 kBq were inserted into LL/2 tumors in C57BL/6 mice and into human-derived A427 or NCI-H520 tumors in athymic mice. The efficacy of the short-lived daughters of 224Ra to produce tumor growth retardation and prolong life was assessed, and the spread of radioisotopes inside tumors was measured using autoradiography. Results: The insertion of a single DART wire into the center of 6- to 7-mm tumors had a pronounced retardation effect on tumor growth, leading to a significant inhibition of 49% (LL2) and 93% (A427) in tumor development and prolongations of 48% (LL2) in life expectancy. In the human model, more than 80% of the treated tumors disappeared or shrunk. Autoradiographic analysis of the treated sectioned tissue revealed the intratumoral distribution of the radioisotopes, and histological analysis showed corresponding areas of necrosis. In vitro experiments demonstrated a dose-dependent killing of tumors cells exposed to alpha particles. Conclusions: Short-lived diffusing alpha-emitters produced tumor growth retardation and increased survival in mice bearing lung tumor implants. These results justify further investigations with improved dose distributions.

  4. Expansion of peripheral and intratumoral regulatory T-cells in hepatocellular carcinoma: A case-control study

    Directory of Open Access Journals (Sweden)

    Sapna Thakur

    2011-01-01

    Full Text Available Background: Hepatocellular carcinoma (HCC is notorious for poor prognosis with limited therapeutic options. A better understanding of the role of regulatory T-cells (Tregs in HCC is important for design of immunotherapy based clinical protocol. The objective of the present study was to evaluate the presence of Tregs in tumor microenvironment in patients with HCC compared to chronic hepatitis (CH. Materials and Methods: The frequency of CD4 + CD25 + Treg cells was evaluated from peripheral blood (PB of 28 patients of HCC and 30 controls including CH cases and healthy donors using flowcytometry. Intratumoral Treg were also analyzed in tissue samples from 17 HCC cases and 15 CH cases. In addition the expression of FOXP3 and CTLA-4 was also studied by RT-PCR. Results: Frequency of CD4 + CD25 + cells in the PBMCs of HCC cases was significantly higher than in HC (10.8 ± 7.64 vs 3.05 ± 1.30, P < 0.005 and CH patients (2.88 ± 1.92, P < 0.005. Also Treg population was significantly higher in HCC tumor microenvironment compared to CH biopsies (15.8 ± 5.32 vs 5.51 ± 3.40, P < 0.05. Expression of FOXP3 and CTLA-4 was also significantly higher in HCC patients ( P < 0.05 compared to CH group. Conclusions: We provide evidence of an increased population of Treg not only in the PB but also in tumor microenvironment of HCC patients, suggesting association of enhanced Treg activity with poor immune responses to tumor antigens. These findings may in future play a significant role in designing immunotherapeutic approaches in HCC.

  5. Epigenetic mechanisms in drug addiction

    OpenAIRE

    Renthal, William; Nestler, Eric J.

    2008-01-01

    Changes in gene expression in brain reward regions are thought to contribute to the pathogenesis and persistence of drug addiction. Recent studies have begun to focus on the molecular mechanisms by which drugs of abuse and related environmental stimuli, such as drug-associated cues or stress, converge on the genome to alter specific gene programs. Increasing evidence suggests that these stable gene expression changes in neurons are mediated in part by epigenetic mechanisms that alter chromati...

  6. Drug Facts

    Medline Plus

    Full Text Available ... People Drug Abuse Hurts Families Drug Abuse Hurts Kids Drug Abuse Hurts Unborn Children Drug Abuse Hurts ... Children and Teens Stay Drug-Free Talking to Kids About Drugs: What To Say if You Were ...

  7. Combination of External Beam Radiotherapy (EBRT) With Intratumoral Injection of Dendritic Cells as Neo-Adjuvant Treatment of High-Risk Soft Tissue Sarcoma Patients

    Energy Technology Data Exchange (ETDEWEB)

    Finkelstein, Steven E., E-mail: steven.finkelstein@moffitt.org [H. Lee Moffitt Cancer Center, Tampa, FL (United States); Iclozan, Cristina; Bui, Marilyn M.; Cotter, Matthew J.; Ramakrishnan, Rupal; Ahmed, Jamil; Noyes, David R.; Cheong, David; Gonzalez, Ricardo J.; Heysek, Randy V.; Berman, Claudia; Lenox, Brianna C.; Janssen, William; Zager, Jonathan S.; Sondak, Vernon K.; Letson, G. Douglas; Antonia, Scott J. [H. Lee Moffitt Cancer Center, Tampa, FL (United States); Gabrilovich, Dmitry I., E-mail: dmitry.gabrilovich@moffitt.org [H. Lee Moffitt Cancer Center, Tampa, FL (United States)

    2012-02-01

    Purpose: The goal of this study was to determine the effect of combination of intratumoral administration of dendritic cells (DC) and fractionated external beam radiation (EBRT) on tumor-specific immune responses in patients with soft-tissue sarcoma (STS). Methods and Material: Seventeen patients with large (>5 cm) high-grade STS were enrolled in the study. They were treated in the neoadjuvant setting with 5,040 cGy of EBRT, split into 28 fractions and delivered 5 days per week, combined with intratumoral injection of 10{sup 7} DCs followed by complete resection. DCs were injected on the second, third, and fourth Friday of the treatment cycle. Clinical evaluation and immunological assessments were performed. Results: The treatment was well tolerated. No patient had tumor-specific immune responses before combined EBRT/DC therapy; 9 patients (52.9%) developed tumor-specific immune responses, which lasted from 11 to 42 weeks. Twelve of 17 patients (70.6%) were progression free after 1 year. Treatment caused a dramatic accumulation of T cells in the tumor. The presence of CD4{sup +} T cells in the tumor positively correlated with tumor-specific immune responses that developed following combined therapy. Accumulation of myeloid-derived suppressor cells but not regulatory T cells negatively correlated with the development of tumor-specific immune responses. Experiments with {sup 111}In labeled DCs demonstrated that these antigen presenting cells need at least 48 h to start migrating from tumor site. Conclusions: Combination of intratumoral DC administration with EBRT was safe and resulted in induction of antitumor immune responses. This suggests that this therapy is promising and needs further testing in clinical trials design to assess clinical efficacy.

  8. Recombinant AAV-mediated HSVtk gene transfer with direct intratumoral injections and Tet-On regulation for implanted human breast cancer

    International Nuclear Information System (INIS)

    HSVtk/ganciclovir (GCV) gene therapy has been extensively studied in tumors and relies largely on the gene expression of HSVtk. Most studies, however, have failed to demonstrate any significant benefit of a controlled gene expression strategy in cancer treatment. The Tet-On system is commonly used to regulate gene expression following Dox induction. We have evaluated the antitumor effect of HSVtk/ganciclovir gene therapy under Tet-On regulation by means of adeno-associated virus-2 (AAV-2)-mediated HSVtk gene transfer with direct intratumoral injections in mice bearing breast cancer tumors. Recombinant adeno-associated virus-2 (rAAV) was constructed and transduced into MCF-7 cell line. GCV treatment to the rAAV infected MCF-7 cells was performed by MTT assay under the doxycycline (Dox) induction or without Dox induction at a vp (viral particle) number of ≥104 /cell. The virus was administered intratumorally to nude mice that had also received GCV intraperitoneally. The antitumor effects were evaluated by measuring tumor regression and histological analysis. We have demonstrated that GCV treatment to the infected MCF-7 cells under the Dox induction was of more inhibited effects than those without Dox induction at ≥104 vp/cell. In ex vivo experiments, tumor growth of BALB/C nude mice breast cancer was retarded after rAAV-2/HSVtk/Tet-On was injected into the tumors under the Dox induction. Infiltrating cells were also observed in tumors after Dox induction followed by GCV treatment and cells were profoundly damaged. The expression of HSVtk gene in MCF-7 cells and BALB/C nude mice tumors was up-regulated by Tet-On under Dox induction with reverse transcription-PCR (RT-PCR) analysis. The antitumor effect of rAAV-mediated HSVtk/GCV gene therapy under the Dox induction with direct intratumoral injections may be a useful treatment for breast cancer and other solid tumors

  9. Immune-mediated regression of established B16F10 melanoma by intratumoral injection of attenuated Toxoplasma gondii protects against rechallenge.

    Science.gov (United States)

    Baird, Jason R; Byrne, Katelyn T; Lizotte, Patrick H; Toraya-Brown, Seiko; Scarlett, Uciane K; Alexander, Matthew P; Sheen, Mee Rie; Fox, Barbara A; Bzik, David J; Bosenberg, Marcus; Mullins, David W; Turk, Mary Jo; Fiering, Steven

    2013-01-01

    Immune recognition of tumors can limit cancer development, but antitumor immune responses are often blocked by tumor-mediated immunosuppression. Because microbes or microbial constituents are powerful adjuvants to stimulate immune responses, we evaluated whether intratumoral administration of a highly immunogenic but attenuated parasite could induce rejection of an established poorly immunogenic tumor. We treated intradermal B16F10 murine melanoma by intratumoral injection of an attenuated strain of Toxoplasma gondii (cps) that cannot replicate in vivo and therefore is not infective. The cps treatment stimulated a strong CD8(+) T cell-mediated antitumor immune response in vivo that regressed established primary melanoma. The cps monotherapy rapidly modified the tumor microenvironment, halting tumor growth, and subsequently, as tumor-reactive T cells expanded, the tumors disappeared and rarely returned. The treatment required live cps that could invade cells and also required CD8(+) T cells and NK cells, but did not require CD4(+) T cells. Furthermore, we demonstrate that IL-12, IFN-γ, and the CXCR3-stimulating cytokines are required for full treatment efficacy. The treatment developed systemic antitumor immune activity as well as antitumor immune memory and therefore might have an impact against human metastatic disease. The approach is not specific for either B16F10 or melanoma. Direct intratumoral injection of cps has efficacy against an inducible genetic melanoma model and transplantable lung and ovarian tumors, demonstrating potential for broad clinical use. The combination of efficacy, systemic antitumor immune response, and complete attenuation with no observed host toxicity demonstrates the potential value of this novel cancer therapy. PMID:23225891

  10. A limited overlap between intratumoral distribution of 1-(5-fluoro-5-deoxy-α-D-arabinofuranosyl)-2-nitroimidazole and copper-diacetyl-bis[N(4)-methylthiosemicarbazone].

    Science.gov (United States)

    Furukawa, Takako; Yuan, Qinghua; Jin, Zhao-Hui; Aung, Winn; Yoshii, Yukie; Hasegawa, Sumitaka; Endo, Hiroko; Inoue, Masahiro; Zhang, Ming-Rong; Fujibayashi, Yasuhisa; Saga, Tsuneo

    2015-09-01

    Positron emission tomography (PET) imaging of tumor hypoxia provides valuable information for cancer treatment planning. Two types of PET tracers, nitroimidazole compounds and [62,64Cu] copper-diacetyl-bis[N(4)-methylthio- semicarbazone] (Cu-ATSM), have been used for imaging hypoxic tumors. High accumulation of these tracers in tumors was shown to predict poor prognosis. Both similar and different intratumoral distributions of these PET tracers have been reported with some studies questioning the dependence of the Cu-ATSM accumulation on hypoxia. In the present study, we compared the intratumoral distribution and cellular uptake of 1-(5-fluoro-5-deoxy-α-D-arabinofuranosyl)-2-nitroimidazole (FAZA) and Cu-ATSM. Intratumoral distributions of FAZA and Cu-ATSM compared by double tracer autoradiography in xenografts of 8 cancer cell lines and 3 cancer tissue originated spheroids (CTOSs) showed that only a limited overlap was observed between the regions with high levels of FAZA and Cu-ATSM accumulation in all the xenografts. Immunohistochemistry in the regions enriched with FAZA and Cu-ATSM in xenografts demonstrated that pimonidazole adducts were in regions that accumulated high levels of FAZA, while HIF-1α was in areas enriched with either tracer. In addition, we examined the cellular uptake of FAZA and Cu-ATSM at different levels of oxygen concentration in 4 cell lines and revealed that cellular uptake of FAZA was increased with the decrease of oxygen concentration from 20 to 2 and from 2 to 1%, while the Cu-ATSM uptake increased with the decrease of oxygen concentration from 20 to 2%, but did not increase with the decrease from 2 to 1%. Our findings indicate that intratumoral distributions of FAZA and Cu-ATSM were essentially non-overlapping and although hypoxia affects the buildup of both tracers, the accumulation of Cu-ATSM occurred at milder hypoxia compared to the conditions required for the accumulation of FAZA. Therefore, accumulation levels of FAZA and

  11. Altered states: psychedelics and anesthetics.

    Science.gov (United States)

    Icaza, Eduardo E; Mashour, George A

    2013-12-01

    The psychedelic experience has been reported since antiquity, but there is relatively little known about the underlying neural mechanisms. A recent neuroimaging study on psilocybin revealed a pattern of decreased cerebral blood flow and functional disconnections that is surprisingly similar to that caused by various anesthetics. In this article, the authors review historical examples of psychedelic experiences induced by general anesthetics and then contrast the mechanisms by which these two drug classes generate altered states of consciousness. PMID:24061599

  12. Oral alterations among chemical dependents

    Directory of Open Access Journals (Sweden)

    Estela Vanessa COLODEL

    2009-03-01

    Full Text Available Introduction: It has been daily observed a significant increase ofchemical dependent individuals, as well as the lack of depth on thisissue in the dentistry area. Nevertheless many times the dentalclinicians are the first professionals to diagnose possible alterations,which appear due to the consumption of tobacco, alcohol and other illicit drugs. Objectives: To make a literature review of oral alterations and to identify them on a specific group of persons, which are addicted to different types of drugs. Material and methods: The clinical history of the selected individuals was added to the answers of a questionnaire,comprising the data of the present research. Results: Besides other minor soft tissue alterations, a high prevalence of caries and periodontal diseases were found in the studied population. Conclusion: It was concluded that the role of the dental clinician is very important to the health rehabilitation of drug addicts, individuals with physical and mental disorders that need specific oral care, which sometimes is neglected.

  13. Two-Step Delivery: Exploiting the Partition Coefficient Concept to Increase Intratumoral Paclitaxel Concentrations In vivo Using Responsive Nanoparticles

    OpenAIRE

    Aaron H. Colby; Rong Liu; Morgan D. Schulz; Padera, Robert F.; Colson, Yolonda L.; Grinstaff, Mark W.

    2016-01-01

    Drug dose, high local target tissue concentration, and prolonged duration of exposure are essential criteria in achieving optimal drug performance. However, systemically delivered drugs often fail to effectively address these factors with only fractions of the injected dose reaching the target tissue. This is especially evident in the treatment of peritoneal cancers, including mesothelioma, ovarian, and pancreatic cancer, which regularly employ regimens of intravenous and/or intraperitoneal c...

  14. Intra-tumoral Heterogeneity of KRAS and BRAF Mutation Status in Patients with Advanced Colorectal Cancer (aCRC and Cost-Effectiveness of Multiple Sample Testing

    Directory of Open Access Journals (Sweden)

    Susan D. Richman

    2011-01-01

    Full Text Available KRAS mutation status is established as a predictive biomarker of benefit from anti-EGFr therapies. Mutations are normally assessed using DNA extracted from one formalin-fixed, paraffin-embedded (FFPE tumor block. We assessed heterogeneity of KRAS and BRAF mutation status intra-tumorally (multiple blocks from the same primary tumor. We also investigated the utility and efficiency of genotyping a ‘DNA cocktail’ prepared from multiple blocks. We studied 68 consenting patients in two randomized clinical trials. DNA was extracted, from ≥2 primary tumor FFPE blocks per patient. DNA was genotyped by pyrosequencing for KRAS codons 12, 13 and 61 and BRAF codon 600. In patients with heterogeneous mutation status, DNA cocktails were prepared and genotyped. Among 69 primary tumors in 68 patients, 7 (10.1% showed intratumoral heterogeneity; 5 (7.2% at KRAS codons 12, 13 and 2 (2.9% at BRAF codon 600. In patients displaying heterogeneity, the relevant KRAS or BRAF mutation was also identified in ‘DNA cocktail’ samples when including DNA from mutant and wild-type blocks. Heterogeneity is uncommon but not insignificant. Testing DNA from a single block will wrongly assign wild-type status to 10% patients. Testing more than one block, or preferably preparation of a ‘DNA cocktail’ from two or more tumor blocks, improves mutation detection at minimal extra cost.

  15. Synthesis, characterization, and magnetically guided antiproliferative activity studies of drug-loaded superparamagnetic nanovectors

    Science.gov (United States)

    Luna, Carlos; Vázquez Ortega, Salvador; Barriga-Castro, Enrique Díaz; Mendoza-Reséndez, Raquel; Gómez-Treviño, Alberto

    2015-05-01

    Commonly, the key players in anticancer therapies and, more specifically, antineoplastic drugs display poor water solubility and slow dissolution rates. As a consequence, they present low bioavailability, poor tissue distribution, and unfavorable pharmacokinetic profiles, limiting their use. To overcome these barriers and improve efficacy, various drug formulations and delivery strategies have been developed. For example, nanoparticles can be used as drug delivery vehicles and current research is encouraging. However, the intra-tumoral diffusion of functionalized nanovehicles remains to be achieved. In the present study, the anticancer drug paclitaxel was loaded into superparamagnetic nanoparticles and characterized. Novel in vitro experiments based on one or two layers of cells revealed important information about the conditions required to achieve efficient drug intra-tumoral diffusion, using these superparamagnetic nanovectors, once they have been localized by external magnetic fields. These studies indicated that ultralow concentrations of paclitaxel (i.e., tenths of ng/μl) significantly reduce the viability of neoplastic cells when they are delivered with control using these nanovectors. Moreover, we showed that a discontinuous application of a magnetic field promotes the localization of the nanoparticles in a targeted region and favors the subsequent dissemination of the nanoparticles between cellular layers.

  16. Drug Facts

    Medline Plus

    Full Text Available ... Addiction? Addiction Risk Factors Does Addiction Run in Families? Why Is It So Hard to Quit Drugs? ... Drug Abuse Hurts Other People Drug Abuse Hurts Families Drug Abuse Hurts Kids Drug Abuse Hurts Unborn ...

  17. Drug Facts

    Medline Plus

    Full Text Available ... Abuse Hurts Unborn Children Drug Abuse Hurts Your Health Drug Abuse Hurts Bodies Drug Abuse Hurts Brains Drug Abuse and Mental Health Problems Often Happen Together The Link Between Drug ...

  18. Drug Facts

    Medline Plus

    Full Text Available ... Health Drug Abuse Hurts Bodies Drug Abuse Hurts Brains Drug Abuse and Mental Health Problems Often Happen Together The Link Between Drug Abuse and HIV/AIDS Recovery & Treatment Drug Treatment Facts Does Drug Treatment Work? Types of Drug Treatment What Is a Relapse? ...

  19. Prescription Drugs and Cold Medicines

    Science.gov (United States)

    ... Drug Abuse: Some medications have psychoactive (mind-altering) properties and, because of that, are sometimes abused—that ... central nervous system (CNS) depressants (for anxiety and sleep disorders), and stimulants (for ADHD and narcolepsy). Opioids ...

  20. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... chances of unsafe behavior by altering judgment and decision-making. To learn about HIV among youth, please visit: http://www.cdc.gov/hiv/risk/age/youth/index.html​ . Resources Publications Drug Facts: HIV/ ...

  1. Drug allergies

    Science.gov (United States)

    Allergic reaction - drug (medication); Drug hypersensitivity; Medication hypersensitivity ... A drug allergy involves an immune response in the body that produces an allergic reaction to a medicine. The ...

  2. Serious drug interactions.

    Science.gov (United States)

    Aronson, J

    1993-10-01

    Of the many varieties of drug interactions, which occur when the disposition or actions of one drug are changed by another, only a few are serious or potentially fatal. A representative outline of some of these illustrates the problem. Precipitant drugs are those which produce the interaction, and object drugs are those whose effects are changed. The interactions which are usually significant are those which alter the metabolism, involve renal excretion, or change the effects of the object drug, especially when the object drug has a low therapeutic index (cardiovascular drugs, anticoagulants, drugs acting on the brain, hypoglycemic drugs, hormones, and cytotoxic drugs). Warfarin toxicity, for example, is produced by aspirin, phenylbutazone, and azapropazone. The dosage requirements of warfarin are reduced by chloramphenicol, ciprofloxacin and other quinolones, erythromycin and some of the other macrolides, metronidazole and other imidazoles, tetracyclines, amiodarone, cimetidine (but not ranitidine), and fibrates. Potassium-depleting drugs can potentiate the action of digoxin, and the elimination of digoxin can be reduced by amiodarone, propafenone, quinidine, and verapamil. Combined oral contraceptives can lose effectiveness through the interaction of carbamazepine, griseofulvin, phenytoin, or rifampicin, which increase estrogen metabolism. In addition, broad-spectrum antibiotics such as ampicillin or tetracyclines also reduce contraceptive effectiveness by altering gut absorption. Even a single drink of an alcoholic beverage may be dangerous to people taking antidepressants, antihistamines, antipsychotic drugs, benzodiazepines, or lithium. Antihistamines suffer inhibited metabolism in the liver if taken in conjunction with the antifungal imidazoles and some of the macrolide antibiotics. Cardiotoxicity of antihistamines is also enhanced by drugs with similar cardiotoxic effects. Lithium potentiation is enhanced by the new serotonin-reuptake inhibitors, and lithium

  3. Histone Acetylation in Drug Addiction

    OpenAIRE

    Renthal, William; Nestler, Eric J.

    2009-01-01

    Regulation of chromatin structure through post-translational modifications of histones (e.g. acetylation) has emerged as an important mechanism to translate a variety of environmental stimuli, including drugs of abuse, into specific changes in gene expression. Since alterations in gene expression are thought to contribute to the development and maintenance of the addicted state, recent efforts are aimed at identifying how drugs of abuse alter chromatin structure and the enzymes which regulate...

  4. Club Drugs

    Science.gov (United States)

    ... uses. Other uses of these drugs are abuse. Club drugs are also sometimes used as "date rape" drugs, to make someone unable to say no to or fight back against sexual assault. Abusing these drugs can ...

  5. Generic Drugs

    Science.gov (United States)

    ... name drug. A brand- name drug has a patent. When the patent runs out— usually after 10 to 14 years— ... if you do not have drug coverage. Condition Diabetes Heart failure High cholesterol Migraine Brand-name drug ...

  6. Drug Facts

    Science.gov (United States)

    ... text to you. This web site talks about drug abuse, addiction and treatment. Watch Videos Information About Drugs Alcohol ... of the drug. "Max" was addicted to prescription drugs. The addiction slowly took over his life. I need different ...

  7. Drug-induced hyperkalemia.

    Science.gov (United States)

    Ben Salem, Chaker; Badreddine, Atef; Fathallah, Neila; Slim, Raoudha; Hmouda, Houssem

    2014-09-01

    Hyperkalemia is a common clinical condition that can be defined as a serum potassium concentration exceeding 5.0 mmol/L. Drug-induced hyperkalemia is the most important cause of increased potassium levels in everyday clinical practice. Drug-induced hyperkalemia may be asymptomatic. However, it may be dramatic and life threatening, posing diagnostic and management problems. A wide range of drugs can cause hyperkalemia by a variety of mechanisms. Drugs can interfere with potassium homoeostasis either by promoting transcellular potassium shift or by impairing renal potassium excretion. Drugs may also increase potassium supply. The reduction in renal potassium excretion due to inhibition of the renin-angiotensin-aldosterone system represents the most important mechanism by which drugs are known to cause hyperkalemia. Medications that alter transmembrane potassium movement include amino acids, beta-blockers, calcium channel blockers, suxamethonium, and mannitol. Drugs that impair renal potassium excretion are mainly represented by angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, direct renin inhibitors, nonsteroidal anti-inflammatory drugs, calcineurin inhibitors, heparin and derivatives, aldosterone antagonists, potassium-sparing diuretics, trimethoprim, and pentamidine. Potassium-containing agents represent another group of medications causing hyperkalemia. Increased awareness of drugs that can induce hyperkalemia, and monitoring and prevention are key elements for reducing the number of hospital admissions, morbidity, and mortality related to drug-induced hyperkalemia.

  8. Predictive value of intratumoral heterogeneity of F-18 FDG uptake for characterization of thyroid nodules according to Bethesda categories of fine needle aspiration biopsy results.

    Science.gov (United States)

    Kim, Seong-Jang; Chang, Samuel

    2015-12-01

    The current study was aimed to investigate the clinical value of intratumoral heterogeneity of F-18 FDG uptake for characterization of thyroid nodule (TN) with inconclusive fine-needle aspiration biopsy (FNAB) results. The current study enrolled 200 patients who showed F-18 FDG incidentaloma and were performed FNAB. The intratumoral heterogeneity of F-18 FDG uptake was represented as the heterogeneity factor (HF), defined as the derivative (dV/dT) of a volume-threshold function for a primary tumor. The diagnostic and predictive values of HF and F-18 FDG PET/CT parameters were evaluated for characterization of inconclusive FNAB results. Among F-18 FDG PET/CT parameters, SUVmax, MTV, and TLG of malignant group were statistically higher than those of Bethesda category of suspicious malignant group. However, HF values were not statistically different between the groups of Bethesda categories (Kruskal-Wallis statistics, 9.924; p = 0.0774). In ROC analysis, when HF > 2.751 was used as cut-off value, the sensitivity and specificity for prediction of malignant TN were 100 % (95 % CI 69.2-100 %) and 60 % (95 % CI 42.1-76.1 %), respectively. The AUC was 0.826 (95 % CI 0.684-0.922) and standard error was 0.0648 (p F-18 FDG uptake represented by HF could be a predictor for characterization of TN with inconclusive FNAB results. Additional large population-based prospective studies are needed to validate the diagnostic utility of HF of F-18 FDG PET/CT.

  9. Drug Facts

    Medline Plus

    Full Text Available ... Drug Abuse Hurts Other People Drug Abuse Hurts Families Drug Abuse Hurts Kids Drug Abuse Hurts Unborn Children ... a Relapse? Find Treatment/Rehab Resources Friends and Family Can Help Prevent Drug Abuse Help Children and Teens Stay Drug-Free ...

  10. CT-guided percutaneous intratumoral chemotherapy with a novel cisplatin/epinephrine injectable gel for the treatment of unresectable malignant liver tumors; CT-gesteuerte perkutane intratumorale Chemotherapie mit Cisplatin-/Adrenalin-Gel zur Behandlung inoperabler maligner Lebertumoren. Ergebnisse einer klinischen Phase-II-Pruefung

    Energy Technology Data Exchange (ETDEWEB)

    Engelmann, K.; Mack, M.G.; Straub, R.; Eichler, K.; Zangos, S.; Vogl, T.J. [Universitaetsklinikum Frankfurt (Germany). Inst. fuer Diagnostische und Interventionelle Radiologie; Orenberg, E. [Matrix Pharmaceutical Inc., Fremont, CA (United States)

    2000-12-01

    Purpose: To evaluate prospectively the volumetric changes of tumor and necrosis in unresectable malignant liver tumors and the clinical aspects after CT-guided direct intratumoral administration of a novel cisplatin/epinephrine injectable gel in a clinical phase II study. Patients and methods: 8 patients with 17 colorectal liver metastases with a mean volume of 42 ml were treated with a mean of 5.1 injections and 8 patients with 11 HCC nodules (mean volume of 22.1 ml) with a mean of 3.25 treatments with CT-guided local administration of a novel cisplatin/epinephrine gel. This method of administration provides a higher local and lower systemic drug concentration. Volumes of tumor and necrosis prior to and after treatment were measured by computer-generated volumetric analysis. Results: Contrast-enhanced studies verified pretherapeutic tumor necrosis with a value of 12.6% in the metastases and 0.6% in the HCC nodules. Intratumoral drug administration resulted in a necrotic volume of 110% in metastases and 128% in HCC versus the mean initial tumor volume, at least 4 treatments resulted in 122% necrosis in metastases and 130% in HCC. Local therapy control rate for the follow-up to 6 months was 38% and 83.3% for the group of metastases and HCC, respectively. Conclusions: Direct intratumoral injection of a novel cisplatin/epinephrine injectable gel results in an induction of a relevant necrosis in malignant liver tumors, with a substantially higher local therapy control rate for HCC compared to colorectal metastases. (orig.) [German] Zielsetzung: Evaluation der Volumenaenderungen von Tumor und Nekrose nach CT-gesteuerter perkutaner intratumoraler Injektion eines neuartigen Cisplatin-/Adrenalin-Gels sowie der klinischen Aspekte diesewr Therapie bei Patienten mit inoperablen malignen Lebertumoren im Rahmen einer klinischen Phase-II-Studie. Patienten und Methoden: 8 Patienten mit 17 kolorektalen Lebermetastasen mit einem mittleren Volumen von 42 ml wurden mit

  11. Prescription Drugs

    Science.gov (United States)

    ... Us Search Search close Teens Teachers Parents Drugs & Health Blog NDAFW Enter Search Term(s): Teens / Drug Facts / Prescription Drugs Prescription Drugs Print What Is Prescription Drug Abuse? Also known as: Opioids: Hillbilly heroin, oxy, OC, oxycotton, percs, happy pills, vikes Depressants: ...

  12. Drug Resistance

    Science.gov (United States)

    HIV Treatment Drug Resistance (Last updated 3/1/2016; last reviewed 3/1/2016) Key Points As HIV multiplies in the ... the risk of drug resistance. What is HIV drug resistance? Once a person becomes infected with HIV, ...

  13. Club Drugs

    Science.gov (United States)

    ... Science Adolescent Brain Comorbidity College-Age & Young Adults Criminal Justice Drugged Driving Drug Testing Drugs and the ... Learn more Statistics and Trends Swipe left or right to scroll. Monitoring the Future Study: Trends in ...

  14. Drug Facts

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    Full Text Available ... Weed, Pot) Facts Meth (Crank, Ice) Facts Pain Medicine (Oxy, Vike) Facts Other Drugs of Abuse What ... About Drugs Alcohol Cocaine Heroin Marijuana Meth Pain Medicines Tobacco Other Drugs You can call 1-800- ...

  15. Drug Reactions

    Science.gov (United States)

    ... problem is interactions, which may occur between Two drugs, such as aspirin and blood thinners Drugs and food, such as statins and grapefruit Drugs and supplements, such as ginkgo and blood thinners ...

  16. Transporters and drug-drug interactions: important determinants of drug disposition and effects.

    Science.gov (United States)

    König, Jörg; Müller, Fabian; Fromm, Martin F

    2013-07-01

    Uptake and efflux transporters determine plasma and tissue concentrations of a broad variety of drugs. They are localized in organs such as small intestine, liver, and kidney, which are critical for drug absorption and elimination. Moreover, they can be found in important blood-tissue barriers such as the blood-brain barrier. Inhibition or induction of drug transporters by coadministered drugs can alter pharmacokinetics and pharmacodynamics of the victim drugs. This review will summarize in particular clinically observed drug-drug interactions attributable to inhibition or induction of intestinal export transporters [P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)], to inhibition of hepatic uptake transporters [organic anion transporting polypeptides (OATPs)], or to inhibition of transporter-mediated [organic anion transporters (OATs), organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATEs), P-gp] renal secretion of xenobiotics. Available data on the impact of nutrition on transport processes as well as genotype-dependent, transporter-mediated drug-drug interactions will be discussed. We will also present and discuss data on the variable extent to which information on the impact of transporters on drug disposition is included in summaries of product characteristics of selected countries (SPCs). Further work is required regarding a better understanding of the role of the drug metabolism-drug transport interplay for drug-drug interactions and on the extrapolation of in vitro findings to the in vivo (human) situation. PMID:23686349

  17. Polymeric micelles as a diagnostic tool for image-guided drug delivery and radiotherapy of HER2 overexpressing breast cancer

    Science.gov (United States)

    Hoang, Nu Bryan

    Block copolymer micelles have emerged as a viable formulation strategy with several drugs relying on this technology in clinical evaluation. To date, information on the tumor penetration and intratumoral distribution of block copolymer micelles (BCM) has been quite limited. Thus, there is impetus to develop a radiolabeled formulation that can be used to gain invaluable insight into the intratumoral distribution of the BCMs. This information could then be used to direct formulation strategies as a means to optimize treatment outcomes. This thesis describes the synthesis and characterization of a targeted block copolymer micelle system based on poly(ethylene glycol)-block -poly(epsilon-caprolactone) labeled with the radionuclide Indium-111 (111In). The incorporation of the imageable component, 111In permits pursuit of image-guided drug delivery for real-time monitoring of tumor localization and intratumoral distribution. Intracellular trafficking of drugs and therapies such as Auger electron emitting radionuclides to perinuclear and nuclear regions of cells is critical to realizing their full therapeutic potential. HER2 specific antibodies (trastuzumab fab fragments) and nuclear localization signal peptides were conjugated to the surface of the BCMs to direct uptake in HER2 expressing cells and subsequent localization in the cell nucleus. Cell uptake was HER2 density dependent, confirming receptor-mediated internalization of the BCMs. Importantly, conjugation of NLS resulted in a significant increase in nuclear uptake of the radionuclide 111In. Successful nuclear targeting was shown to improve the antiproliferative effect of the Auger electrons. In addition, a significant radiation enhancement effect was observed by concurrent delivery of low-dose MTX and 111In in all breast cancer cell lines evaluated. Imaging enabled the accurate quantification of the specific tumor uptake of the micelles and visualization of their degree of tumor penetration in relation to

  18. Drugging Membrane Protein Interactions.

    Science.gov (United States)

    Yin, Hang; Flynn, Aaron D

    2016-07-11

    The majority of therapeutics target membrane proteins, accessible on the surface of cells, to alter cellular signaling. Cells use membrane proteins to transduce signals into cells, transport ions and molecules, bind cells to a surface or substrate, and catalyze reactions. Newly devised technologies allow us to drug conventionally "undruggable" regions of membrane proteins, enabling modulation of protein-protein, protein-lipid, and protein-nucleic acid interactions. In this review, we survey the state of the art of high-throughput screening and rational design in drug discovery, and we evaluate the advances in biological understanding and technological capacity that will drive pharmacotherapy forward against unorthodox membrane protein targets. PMID:26863923

  19. Drug Abuse

    Science.gov (United States)

    ... as drugged driving, violence, stress, and child abuse. Drug abuse can lead to homelessness, crime, and missed work or problems with keeping a job. It harms unborn babies and destroys families. There are different types of treatment for drug abuse. But the best is to prevent drug ...

  20. Drug Facts

    Medline Plus

    Full Text Available ... text to you. This web site talks about drug abuse, addiction and treatment. Watch Videos Information About Drugs Alcohol ... of the drug. "Max" was addicted to prescription drugs. The addiction slowly took over his life. I need different ...

  1. Successful Intravascular Correction of Intratumoral Pseudoaneurysm by Erosion of the Aorta in a Patient with Thoracic Giant Cell Tumor of Bone Responding to Denosumab

    Directory of Open Access Journals (Sweden)

    Natalia M. P. Fraile

    2015-01-01

    Full Text Available Giant cell tumor of bone (GCT is a rare, locally aggressive neoplasm characterized by the presence of giant cells with osteoclast activity. Its biology involves the overexpression of the Receptor Activator of Nuclear Factor kB Ligand (RANKL by osteoclast-like giant cells and tumor stromal cells, which has been shown to be an actionable target in this disease. In cases amenable to surgical resection, very few therapeutic options were available until the recent demonstration of significant activity of the anti-RANK-ligand monoclonal antibody denosumab. Here we present a case of a patient with advanced GCT arising in the spine, recurring after multiple resections and embolization. Following initiation of denosumab, which resulted in unequivocal clinical improvement, computed tomography of the chest done for reassessment purposes revealed an intratumoral pseudoaneurysm by erosion of the aorta, further corrected by endovascular approach and stent placement. Patient had an unremarkable recovery from the procedure and continued benefit from therapy with denosumab and remains on treatment 24 months after the first dose.

  2. Intratumor heterogeneous distribution of neutron capture compounds suggested by the radiobiological findings concerning sensitivity, repair, reoxygenation and recruitment following neutron capture reaction

    Energy Technology Data Exchange (ETDEWEB)

    Masunaga, Shin-ichiro [Kyoto Univ., Kumatori, Osaka (Japan). Research Reactor Inst

    2000-10-01

    There are many quiescent cells (Q cells) in human solid tumor in comparison with an experimental animal tumor. The control of the Q cells by irradiation is more difficult than the control of proliferous cells (P cells). Recurrence of solid tumor after irradiation therapy is considered as that the uncontrolled Q cells by irradiation proliferate again. One of the most important issues in tumor therapy is to develop a method which destroys effectively the Q cells in solid tumors. Subcutaneous injection of BrdU into mice transplanted SCCV II tumor is carried out in order to mark all of the proliferous cells during 5 days. Neutron capture compound, sodium borocaptate{sup -10}B (BSH) 125 mg/kg, or dl-p-boronophenylalanine-{sup 10}B(BPA) 1500 mg/kg is dosed to the mice. For a series of tests which include sensitivity, potentially lethal damage repair (PLDR), reoxygenation and recruitment of the tumor cells, the mice are irradiated by thermal neutron and gamma-ray with various absorbed doses. The results show that the neutron capture compound concentration in the Q cells, particularly BPA is lower than the concentration in total intratumor cells (P+Q cells). The sensitivity of the Q cells is lower than the P+Q cells, and the PLDR capacity of the Q cells is larger than the P+Q cells. (Suetake, M.)

  3. Downstream mediators of the intratumoral interferon response suppress antitumor immunity, induce gemcitabine resistance and associate with poor survival in human pancreatic cancer.

    Science.gov (United States)

    Delitto, Daniel; Perez, Chelsey; Han, Song; Gonzalo, David H; Pham, Kien; Knowlton, Andrea E; Graves, Christina L; Behrns, Kevin E; Moldawer, Lyle L; Thomas, Ryan M; Liu, Chen; George, Thomas J; Trevino, Jose G; Wallet, Shannon M; Hughes, Steven J

    2015-12-01

    The cancer microenvironment allows tumor cells to evade immune surveillance through a variety of mechanisms. While interferon-γ (IFNγ) is central to effective antitumor immunity, its effects on the microenvironment are not as clear and have in some cancers been shown to induce immune checkpoint ligands. The heterogeneity of these responses to IFNγ remains poorly characterized in desmoplastic malignancies with minimal inflammatory cell infiltration, such as pancreatic cancer (PC). Thus, the IFNγ response within and on key cells of the PC microenvironment was evaluated. IFNγ induced expression of human leukocyte antigen (HLA) class I and II on PC cell lines, primary pancreatic cancer epithelial cells (PPCE) and patient-derived tumor-associated stroma, concomitant with an upregulation of PDL1 in the absence of CD80 and CD86 expression. As expected, IFNγ also induced high levels of CXCL10 from all cell types. In addition, significantly higher levels of CXCL10 were observed in PC specimens compared to those from chronic pancreatitis, whereby intratumoral CXCL10 concentration was an independent predictor of poor survival. Immunohistochemical analysis revealed a subset of CXCR3-positive cancer cells in over 90 % of PC specimens, as well as on a subset of cultured PC cell lines and PPCE, whereby exposure to CXCL10 induced resistance to the chemotherapeutic gemcitabine. These findings suggest that IFNγ has multiple effects on many cell types within the PC microenvironment that may lead to immune evasion, chemoresistance and shortened survival.

  4. Analgesic drugs

    OpenAIRE

    Kerec Kos, Mojca

    2015-01-01

    In the management of pain analgesic drugs are chosen regarding the intensity and type of pain. The selection of analgesic drug depends on pharmacokinetic properties of the drug and available pharmaceutical dosage forms. Beside non-opioid analgesics (non-steroidal antiinflammatory drugs, acetaminophen), opioid analgesic drugs have an important role in the treatment of pain. Pri zdravljenju bolečine izberemo analgetik glede na jakost in vrsto bolečine. Na izbiro ustreznega analgetika vplivaj...

  5. Intratumoral estrogen sulfotransferase induction contributes to the anti-breast cancer effects of the dithiocarbamate derivative TM208

    Science.gov (United States)

    Ji, Xi-wei; Chen, Guang-ping; Song, Yan; Hua, Ming; Wang, Li-jie; Li, Liang; Yuan, Yin; Wang, Si-yuan; Zhou, Tian-yan; Lu, Wei

    2015-01-01

    Aim: Sulfotransferase-catalyzed sulfation is the most important pathway for inactivating estrogens. Thus, activation of estrogen sulfotransferase (EST) may be an alternative approach for the treatment of estrogen-dependent breast cancer. In this study we investigated the involvement of EST in anti-breast cancer effects of the dithiocarbamate derivative TM208 in vitro and in vivo. Methods: The viability of human breast cancer MCF-7 cells was determined using a SBB assay. Nude mice bearing MCF-7 cells were orally administered TM208 (50 and 150 mg·kg−1·d−1) for 18 days. The xenograft tumors and uteri were collected. The mRNA expression of EST was examined with real-time PCR. EST protein was detected with Western blot, ELISA or immunohistochemical staining assays. A radioactive assay was used to measure the EST activity. Uterotropic bioassay was used to examine the uterine estrogen responses. Results: Treatment with TM208 (10, 15 and 20 μmol/L) concentration-dependently increased EST expression in MCF-7 cells in vitro. Co-treatment with triclosan, an inhibitor of sulfonation, abolished TM208-induced cytotoxicity in MCF-7 cells. TM208 exhibited an apparent anti-estrogenic property: it exerted more potent cytotoxicity in E2-treated MCF-7 cells. In the nude mice bearing MCF-7 cells, TM208 administration time-dependently increased the expression and activity of EST, and blocked the gradual increase of E2 concentration in the xenograft tumors. Furthermore, TM208 administration blocked the estrogens-stimulated uterine enlargement. Tamoxifen, a positive control drug, produced similar effects on the expression and activity of EST in vitro and in vivo. Conclusion: The induction of EST and reduction of estrogen concentration contribute to the anti-breast cancer action of TM208 and tamoxifen. TM208 may be developed as anticancer drug for the treatment of estrogen receptor-positive breast cancer. PMID:25937633

  6. 瘤内磁敏感信号对脑星形细胞瘤术前分级诊断的价值%The Preoprative Diagnostic Value of Intratumoral Susceptibility Signals Level in Grading Cerebral Astrocytomas

    Institute of Scientific and Technical Information of China (English)

    胡茂清; 龙晚生; 龙昉; 周红英; 吴国昌; 罗学毛; 李伟

    2013-01-01

    目的 探讨瘤内磁敏感信号(ITSS)级别对脑星形细胞瘤术前分级诊断的价值.方法 分析39例经手术病理证实为脑星形细胞瘤患者的磁敏感加权成像(SWI)的影像表现,对瘤内ITSS进行分级并判断肿瘤的高、低级别,与病理结果进行对照.结果 11例低级别组星形细胞瘤中,ITSS评分0级6例,1级5例.28例高级别组星形细胞瘤中,ITSS评分1级2例,2级7例,3级19例.高低级别组星形细胞瘤的ITSS级别有统计学差异(Z=-4.986,P<0.01),ITSS级别与星形细胞瘤的病理级别呈正相关(r=0.958,P<0.01).结论 不同级别脑星形细胞瘤内ITSS级别有明显差异,ITSS级别对星形细胞瘤术前分级有重要价值.%Objective To explore the preoprative diagnostic value of intratumoral susceptibility signals(ITSS) level in grading cerebral astrocytomas.Methods The imaging findings of susceptibility weighted imaging (SWI) of 39 patients with pathologically confirmed cerebral astrocytomas were analyzed,scored the intratumoral ITSS level and judged the histopathologic grade of the tumor,then compared with pathological findings.Results Astrocytomas in 11 cases of low grade group,ITSS scored 0 in 6 cases,1 in 5 cases.28 cases of high grade group astrocytomas,ITSS scored 1 in 2 cases,2 in 7 cases and 3 in 19 cases.There was statistical significance in intratumoral ITSS levels between high and low grade group astrocytomas(Z=-4.986,P<0.01),there was positive correlation between the levels of intratumoral ITSS and the grade of astrocytomas(r=0.958,P<0.01).Conclusion Different grades of brain astrocytomas show significantly difference on intratumoral ITSS levels,probably be helpful for evaluation of astrocytomas grading preoperatively.

  7. Substance use - prescription drugs

    Science.gov (United States)

    Substance use disorder - prescription drugs; Substance abuse - prescription drugs; Drug abuse - prescription drugs; Drug use - prescription drugs; Narcotics - substance use; Opioid - substance use; Sedative - substance use; Hypnotic - substance ...

  8. TM9SF4 is a novel V-ATPase-interacting protein that modulates tumor pH alterations associated with drug resistance and invasiveness of colon cancer cells.

    Science.gov (United States)

    Lozupone, F; Borghi, M; Marzoli, F; Azzarito, T; Matarrese, P; Iessi, E; Venturi, G; Meschini, S; Canitano, A; Bona, R; Cara, A; Fais, S

    2015-10-01

    An inverted pH gradient across the cell membranes is a typical feature of malignant cancer cells that are characterized by extracellular acidosis and cytosol alkalization. These dysregulations are able to create a unique milieu that favors tumor progression, metastasis and chemo/immune-resistance traits of solid tumors. A key event mediating tumor cell pH alterations is an aberrant activation of ion channels and proton pumps such as (H+)-vacuolar-ATPase (V-ATPase). TM9SF4 is a poorly characterized transmembrane protein that we have recently shown to be related to cannibal behavior of metastatic melanoma cells. Here, we demonstrate that TM9SF4 represents a novel V-ATPase-associated protein involved in V-ATPase activation. We have observed in HCT116 and SW480 colon cancer cell lines that TM9SF4 interacts with the ATP6V1H subunit of the V-ATPase V1 sector. Suppression of TM9SF4 with small interfering RNAs strongly reduces assembly of V-ATPase V0/V1 sectors, thus reversing tumor pH gradient with a decrease of cytosolic pH, alkalization of intracellular vesicles and a reduction of extracellular acidity. Such effects are associated with a significant inhibition of the invasive behavior of colon cancer cells and with an increased sensitivity to the cytotoxic effects of 5-fluorouracil. Our study shows for the first time the important role of TM9SF4 in the aberrant constitutive activation of the V-ATPase, and the development of a malignant phenotype, supporting the potential use of TM9SF4 as a target for future anticancer therapies.

  9. Drug Facts

    Medline Plus

    Full Text Available ... Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) Facts Marijuana (Weed, Pot) Facts Meth (Crank, Ice) Facts Pain ... Watch Videos Information About Drugs Alcohol Cocaine Heroin Marijuana Meth Pain Medicines Tobacco Other Drugs You can ...

  10. Drug Facts

    Medline Plus

    Full Text Available ... Numbers and Websites Search Share Listen English Español Information about this page Click on the button that ... about drug abuse, addiction and treatment. Watch Videos Information About Drugs Alcohol Cocaine Heroin Marijuana Meth Pain ...

  11. Drug Facts

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    Full Text Available Easy-to-Read Drug Facts Search form Search Menu Home Drugs That People Abuse Alcohol Facts Cigarette and Tobacco Facts Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) Facts Marijuana ( ...

  12. Drug Facts

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    Full Text Available ... People Abuse Alcohol Facts Cigarette and Tobacco Facts Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) Facts Marijuana (Weed, ... and treatment. Watch Videos Information About Drugs Alcohol Cocaine Heroin Marijuana Meth Pain Medicines Tobacco Other Drugs ...

  13. Drug Facts

    Medline Plus

    Full Text Available ... People Abuse Alcohol Facts Cigarette and Tobacco Facts Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) Facts Marijuana ( ... and treatment. Watch Videos Information About Drugs Alcohol Cocaine Heroin Marijuana Meth Pain Medicines Tobacco Other Drugs ...

  14. Drug Facts

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    Full Text Available ... abuse, addiction and treatment. Watch Videos Information About Drugs Alcohol Cocaine Heroin Marijuana Meth Pain Medicines Tobacco ... 662-HELP (4357) at any time to find drug treatment centers near you. I want my daughter ...

  15. Drug Facts

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    Full Text Available ... Bodies Drug Abuse Hurts Brains Drug Abuse and Mental Health Problems Often Happen Together The Link Between ... This Website Tools and Resources | Contact Us | Site Map | Accessibility | Privacy | FOIA (NIH) The National Institute on ...

  16. Drug Facts

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    Full Text Available ... Search form Search Menu Home Drugs That People Abuse Alcohol Facts Cigarette and Tobacco Facts Cocaine (Coke, ... Pain Medicine (Oxy, Vike) Facts Other Drugs of Abuse What is Addiction? Do You or a Loved ...

  17. Drug Facts

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    Full Text Available ... Cigarette and Tobacco Facts Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) Facts Marijuana (Weed, Pot) Facts Meth ( ... treatment. Watch Videos Information About Drugs Alcohol Cocaine Heroin Marijuana Meth Pain Medicines Tobacco Other Drugs You ...

  18. Supramolecular approaches for drug development.

    Science.gov (United States)

    Kawakami, K; Ebara, M; Izawa, H; Sanchez-Ballester, N M; Hill, J P; Ariga, K

    2012-01-01

    Various supramolecular systems can be used as drug carriers to alter physicochemical and pharmacokinetic characteristics of drugs. Representative supramolecular systems that can be used for this purpose include surfactant/polymer micelles, (micro)emulsions, liposomes, layer-by-layer assemblies, and various molecular conjugates. Notably, liposomes are established supramolecular drug carriers, which have already been marketed in formulations including AmBisome(®) (for treatment of fungal infection), Doxil(®) (for Kaposi's sarcoma), and Visudyne(®) (for age-related macular degeneration and choroidal neovascularization). Microemulsions have been used oral drug delivery of poorly soluble drugs due to improvements in bioavailability and predictable of absorption behavior. Neoral(®), an immunosuppressant used after transplant operations, is one of the most famous microemulsion-based drugs. Polymer micelles are being increasingly investigated as novel drug carriers and some formulations have already been tested in clinical trials. Supramolecular systems can be functionalized by designing the constituent molecules to achieve efficient delivery of drugs to desired sites in the body. In this review, representative supramolecular drug delivery systems, that may improve usability of candidate drugs or add value to existing drugs, are introduced. PMID:22455591

  19. A low carbohydrate, high protein diet suppresses intratumoral androgen synthesis and slows castration-resistant prostate tumor growth in mice.

    Science.gov (United States)

    Fokidis, H Bobby; Yieng Chin, Mei; Ho, Victor W; Adomat, Hans H; Soma, Kiran K; Fazli, Ladan; Nip, Ka Mun; Cox, Michael; Krystal, Gerald; Zoubeidi, Amina; Tomlinson Guns, Emma S

    2015-06-01

    Dietary factors continue to preside as dominant influences in prostate cancer prevalence and progression-free survival following primary treatment. We investigated the influence of a low carbohydrate diet, compared to a typical Western diet, on prostate cancer (PCa) tumor growth in vivo. LNCaP xenograft tumor growth was studied in both intact and castrated mice, representing a more advanced castration resistant PCa (CRPC). No differences in LNCaP tumor progression (total tumor volume) with diet was observed for intact mice (P = 0.471) however, castrated mice on the Low Carb diet saw a statistically significant reduction in tumor growth rate compared with Western diet fed mice (P = 0.017). No correlation with serum PSA was observed. Steroid profiles, alongside serum cholesterol and cholesteryl ester levels, were significantly altered by both diet and castration. Specifically, DHT concentration with the Low Carb diet was 58% that of the CRPC-bearing mice on the Western diet. Enzymes in the steroidogenesis pathway were directly impacted and tumors isolated from intact mice on the Low Carb diet had higher AKR1C3 protein levels and lower HSD17B2 protein levels than intact mice on the Western diet (ARK1C3: P = 0.074; HSD17B2: P = 0.091, with α = 0.1). In contrast, CRPC tumors from mice on Low Carb diets had higher concentrations of both HSD17B2 (P = 0.016) and SRD5A1 (P = 0.058 with α = 0.1) enzymes. There was no correlation between tumor growth in castrated mice for Low Carb diet versus Western diet and (a) serum insulin (b) GH serum levels (c) insulin receptor (IR) or (d) IGF-1R in tumor tissue. Intact mice fed Western diet had higher serum insulin which was associated with significantly higher blood glucose and tumor tissue IR. We conclude that both diet and castration have a significant impact on the endocrinology of mice bearing LNCaP xenograft tumors. The observed effects of diet on cholesterol and steroid regulation impact tumor tissue DHT specifically and are

  20. A low carbohydrate, high protein diet suppresses intratumoral androgen synthesis and slows castration-resistant prostate tumor growth in mice.

    Science.gov (United States)

    Fokidis, H Bobby; Yieng Chin, Mei; Ho, Victor W; Adomat, Hans H; Soma, Kiran K; Fazli, Ladan; Nip, Ka Mun; Cox, Michael; Krystal, Gerald; Zoubeidi, Amina; Tomlinson Guns, Emma S

    2015-06-01

    Dietary factors continue to preside as dominant influences in prostate cancer prevalence and progression-free survival following primary treatment. We investigated the influence of a low carbohydrate diet, compared to a typical Western diet, on prostate cancer (PCa) tumor growth in vivo. LNCaP xenograft tumor growth was studied in both intact and castrated mice, representing a more advanced castration resistant PCa (CRPC). No differences in LNCaP tumor progression (total tumor volume) with diet was observed for intact mice (P = 0.471) however, castrated mice on the Low Carb diet saw a statistically significant reduction in tumor growth rate compared with Western diet fed mice (P = 0.017). No correlation with serum PSA was observed. Steroid profiles, alongside serum cholesterol and cholesteryl ester levels, were significantly altered by both diet and castration. Specifically, DHT concentration with the Low Carb diet was 58% that of the CRPC-bearing mice on the Western diet. Enzymes in the steroidogenesis pathway were directly impacted and tumors isolated from intact mice on the Low Carb diet had higher AKR1C3 protein levels and lower HSD17B2 protein levels than intact mice on the Western diet (ARK1C3: P = 0.074; HSD17B2: P = 0.091, with α = 0.1). In contrast, CRPC tumors from mice on Low Carb diets had higher concentrations of both HSD17B2 (P = 0.016) and SRD5A1 (P = 0.058 with α = 0.1) enzymes. There was no correlation between tumor growth in castrated mice for Low Carb diet versus Western diet and (a) serum insulin (b) GH serum levels (c) insulin receptor (IR) or (d) IGF-1R in tumor tissue. Intact mice fed Western diet had higher serum insulin which was associated with significantly higher blood glucose and tumor tissue IR. We conclude that both diet and castration have a significant impact on the endocrinology of mice bearing LNCaP xenograft tumors. The observed effects of diet on cholesterol and steroid regulation impact tumor tissue DHT specifically and are

  1. Medicaid Drugs

    OpenAIRE

    Poisal, John A.

    2004-01-01

    The following commentary unites a collection of articles primarily concerned with prescription drug issues in Medicaid. It also features highlights from a piece outlining Australia's pharmaceutical delivery system. Specifically, in this issue, you will find comprehensive analyses of drug expenditure trends, issues regarding access to pharmaceuticals in Medicaid, and an evaluation of ongoing generic drug cost-containment programs.

  2. Drug Facts

    Medline Plus

    Full Text Available ... Watch Videos Information About Drugs Alcohol Cocaine Heroin Marijuana Meth Pain Medicines Tobacco Other Drugs You can call 1-800-662-HELP (4357) at any time to find drug treatment centers near ... different people around me. To stop using marijuana, "Cristina" is making positive changes in her life. ...

  3. Dissemination of Newcastle Disease Virus (NDV-AF2240 in Liver during Intratumoral Injection of Xenotransplant Breast Cancer in BALB/c Mice

    Directory of Open Access Journals (Sweden)

    Gholamreza Motalleb

    2009-01-01

    Full Text Available Objective: Newcastle disease virus (NDV or avian paramyxovirus type1 possessesseveral unique properties that make it an excellent anticancer agent. The hemagglutininneuraminidase (HN protein of NDV plays an important role in viral infection. Thepurpose of the present study is to investigate the dissemination of Newcastle diseasevirus (NDV AF2240 strain in the liver during intratumoral injection in 4T1 breast cancerin female BALB/c mice.Materials and Methods: A total of 200 female BALB/c mice were divided randomlyinto 10 cancerous groups consisting of 20 mice per group. The mice were initially inducedwith 104 4T1 cells, NDV-AF2240 and tamoxifen co-culture. Cancerous groupswere divided into: cancer control (CC, cancer treated with 0.5 μg/ml tamoxifen citrate(CT, cancer treated with 8, 16, 32 and 64HA units of NDV-AF2240 (respectivelynamed C/NDV8, C/NDV16, C/NDV32, C/NDV64, cancer treated with 8, 16, 32 and64HA units of NDV-AF2240 and tamoxifen (respectively as CT/NDV8, CT/NDV16, CT/NDV32 and CT/NDV64 daily for four weeks. In situ reverse transcription polymerasechain reaction (In situ RT-PCR, negative staining electron microscopy (NSEM, polyclonalchicken antibody and goat anti-chicken antibody conjugated with fluoresceinisothiocynate (FITC using confocal laser scanning microscopy (CLSM were used todetect the virus in the tumor and liver.Results: In situ RT-PCR, NSEM and CLSM successfully detected NDV-AF2240 intumor cells and liver.Conclusion: The findings showed NDV-AF2240 disseminated into liver during intratumoralinjection.

  4. Castration induces up-regulation of intratumoral androgen biosynthesis and androgen receptor expression in an orthotopic VCaP human prostate cancer xenograft model.

    Science.gov (United States)

    Knuuttila, Matias; Yatkin, Emrah; Kallio, Jenny; Savolainen, Saija; Laajala, Teemu D; Aittokallio, Tero; Oksala, Riikka; Häkkinen, Merja; Keski-Rahkonen, Pekka; Auriola, Seppo; Poutanen, Matti; Mäkelä, Sari

    2014-08-01

    Androgens are key factors involved in the development and progression of prostate cancer (PCa), and PCa growth can be suppressed by androgen deprivation therapy. In a considerable proportion of men receiving androgen deprivation therapy, however, PCa progresses to castration-resistant PCa (CRPC), making the development of efficient therapies challenging. We used an orthotopic VCaP human PCa xenograft model to study cellular and molecular changes in tumors after androgen deprivation therapy (castration). Tumor growth was monitored through weekly serum prostate-specific antigen measurements, and mice with recurrent tumors after castration were randomized to treatment groups. Serum prostate-specific antigen concentrations showed significant correlation with tumor volume. Castration-resistant tumors retained concentrations of intratumoral androgen (androstenedione, testosterone, and 5α-dihydrotestosterone) at levels similar to tumors growing in intact hosts. Accordingly, castration induced up-regulation of enzymes involved in androgen synthesis (CYP17A1, AKR1C3, and HSD17B6), as well as expression of full-length androgen receptor (AR) and AR splice variants (AR-V1 and AR-V7). Furthermore, AR target gene expression was maintained in castration-resistant xenografts. The AR antagonists enzalutamide (MDV3100) and ARN-509 suppressed PSA production of castration-resistant tumors, confirming the androgen dependency of these tumors. Taken together, the findings demonstrate that our VCaP xenograft model exhibits the key characteristics of clinical CRPC and thus provides a valuable tool for identifying druggable targets and for testing therapeutic strategies targeting AR signaling in CRPC.

  5. Drug allergy

    Directory of Open Access Journals (Sweden)

    Warrington Richard

    2011-11-01

    Full Text Available Abstract Drug allergy encompasses a spectrum of immunologically-mediated hypersensitivity reactions with varying mechanisms and clinical presentations. This type of adverse drug reaction (ADR not only affects patient quality of life, but may also lead to delayed treatment, unnecessary investigations, and even mortality. Given the myriad of symptoms associated with the condition, diagnosis is often challenging. Therefore, referral to an allergist experienced in the identification, diagnosis and management of drug allergy is recommended if a drug-induced allergic reaction is suspected. Diagnosis relies on a careful history and physical examination. In some instances, skin testing, graded challenges and induction of drug tolerance procedures may be required. The most effective strategy for the management of drug allergy is avoidance or discontinuation of the offending drug. When available, alternative medications with unrelated chemical structures should be substituted. Cross-reactivity among drugs should be taken into consideration when choosing alternative agents. Additional therapy for drug hypersensitivity reactions is largely supportive and may include topical corticosteroids, oral antihistamines and, in severe cases, systemic corticosteroids. In the event of anaphylaxis, the treatment of choice is injectable epinephrine. If a particular drug to which the patient is allergic is indicated and there is no suitable alternative, induction of drug tolerance procedures may be considered to induce temporary tolerance to the drug. This article provides a backgrounder on drug allergy and strategies for the diagnosis and management of some of the most common drug-induced allergic reactions, such allergies to penicillin, sulfonamides, cephalosporins, radiocontrast media, local anesthetics, general anesthetics, acetylsalicylic acid (ASA and non-steroidal anti-inflammatory drugs.

  6. Attention Alters Perceived Attractiveness.

    Science.gov (United States)

    Störmer, Viola S; Alvarez, George A

    2016-04-01

    Can attention alter the impression of a face? Previous studies showed that attention modulates the appearance of lower-level visual features. For instance, attention can make a simple stimulus appear to have higher contrast than it actually does. We tested whether attention can also alter the perception of a higher-order property-namely, facial attractiveness. We asked participants to judge the relative attractiveness of two faces after summoning their attention to one of the faces using a briefly presented visual cue. Across trials, participants judged the attended face to be more attractive than the same face when it was unattended. This effect was not due to decision or response biases, but rather was due to changes in perceptual processing of the faces. These results show that attention alters perceived facial attractiveness, and broadly demonstrate that attention can influence higher-level perception and may affect people's initial impressions of one another. PMID:26966228

  7. [Liver damage caused by drugs].

    Science.gov (United States)

    Strohmeyer, G; Weik, C

    1999-05-01

    The liver has a central role in the metabolism of many drugs, since this organ is the main site of biotransformation of endo- and xenobiotics. Water-soluble drugs have a small volume of distribution and can be eliminated unchanged in the urine. By contrast, lipid-soluble drugs have a larger volume of distribution and require conversion to water-soluble metabolites for their elimination in urine or bile. The liver with its specific receptors, transporters and enzymes is responsible for the uptake, transformation and excretion of the lipophilic drugs. While most of the drugs are transformed into stable metabolites, other drugs form reactive, potentially toxic, metabolites producing liver cell damage. Liver injury caused by drugs may mimic almost any kind of liver disease. Clinical findings are gastrointestinal symptoms with nausea, vomiting and abdominal pain, cholestatic liver injury with jaundice and pruritus of severe inflammatory and cirrhotic liver damage with signs of liver failure, encephalopathy and cerebral edema. The morphological changes vary from hepatitis, cholestasis, fatty liver, granulomatous hepatitis, peri-/portal inflammation, to fibrosis with cirrhotic alterations and vascular lesions and tumors. The most commonly used drugs causing severe liver injury are discussed in detail. These are anabolics, oral contraceptives, antituberculous and antifungal agents, nonsteroidal anti-inflammatory drugs, ring substituted amphetamins ("designer drugs"), antiarrhythmics and antibiotics.

  8. Characterization of Schizophrenia Adverse Drug Interactions through a Network Approach and Drug Classification

    Directory of Open Access Journals (Sweden)

    Jingchun Sun

    2013-01-01

    Full Text Available Antipsychotic drugs are medications commonly for schizophrenia (SCZ treatment, which include two groups: typical and atypical. SCZ patients have multiple comorbidities, and the coadministration of drugs is quite common. This may result in adverse drug-drug interactions, which are events that occur when the effect of a drug is altered by the coadministration of another drug. Therefore, it is important to provide a comprehensive view of these interactions for further coadministration improvement. Here, we extracted SCZ drugs and their adverse drug interactions from the DrugBank and compiled a SCZ-specific adverse drug interaction network. This network included 28 SCZ drugs, 241 non-SCZs, and 991 interactions. By integrating the Anatomical Therapeutic Chemical (ATC classification with the network analysis, we characterized those interactions. Our results indicated that SCZ drugs tended to have more adverse drug interactions than other drugs. Furthermore, SCZ typical drugs had significant interactions with drugs of the “alimentary tract and metabolism” category while SCZ atypical drugs had significant interactions with drugs of the categories “nervous system” and “antiinfectives for systemic uses.” This study is the first to characterize the adverse drug interactions in the course of SCZ treatment and might provide useful information for the future SCZ treatment.

  9. Potential prostate cancer drug target: bioactivation of androstanediol by conversion to dihydrotestosterone.

    Science.gov (United States)

    Mohler, James L; Titus, Mark A; Wilson, Elizabeth M

    2011-09-15

    High-affinity binding of dihydrotestosterone (DHT) to the androgen receptor (AR) initiates androgen-dependent gene activation, required for normal male sex development in utero, and contributes to prostate cancer development and progression in men. Under normal physiologic conditions, DHT is synthesized predominantly by 5α-reduction of testosterone, the major circulating androgen produced by the testis. During androgen deprivation therapy, intratumoral androgen production is sufficient for AR activation and prostate cancer growth, even though circulating testicular androgen levels are low. Recent studies indicate that the metabolism of 5α-androstane-3α, 17β-diol by 17β-hydroxysteroid dehydrogenase 6 in benign prostate and prostate cancer cells is a major biosynthetic pathway for intratumoral synthesis of DHT, which binds AR and initiates transactivation to promote prostate cancer growth during androgen deprivation therapy. Drugs that target the so-called backdoor pathway of DHT synthesis provide an opportunity to enhance clinical response to luteinizing-hormone-releasing hormone (LHRH) agonists or antagonists, AR antagonists, and inhibitors of 5α-reductase enzymes (finasteride or dutasteride), and other steroid metabolism enzyme inhibitors (ketoconazole or the recently available abiraterone acetate). PMID:21705451

  10. [Pharmacogenetics and tailored drug therapy

    DEFF Research Database (Denmark)

    Nielsen, F.C.; Borregaard, N.

    2009-01-01

    Pharmacogenetics traditionally designates the study of genetically determined variation in metabolism of drugs and toxins from the environment. The concept of phamacogenetics has been widened to encompass how essential genetic alterations central to the development of diseases may by used to target...

  11. Orphan drugs

    Directory of Open Access Journals (Sweden)

    Goločorbin-Kon Svetlana

    2013-01-01

    Full Text Available Introduction. Drugs used for treatment of rare diseases are known worldwide under the term of orphan drugs because pharmaceutical companies have not been interested in ”adopting” them, that is in investing in research, developing and producing these drugs. This kind of policy has been justified by the fact that these drugs are targeted for small markets, that only a small number of patients is available for clinical trials, and that large investments are required for the development of drugs meant to treat diseases whose pathogenesis has not yet been clarified in majority of cases. The aim of this paper is to present previous and present status of orphan drugs in Serbia and other countries. The beginning of orphan drugs development. This problem was first recognized by Congress of the United States of America in January 1983, and when the ”Orphan Drug Act” was passed, it was a turning point in the development of orphan drugs. This law provides pharmaceutical companies with a series of reliefs, both financial ones that allow them to regain funds invested into the research and development and regulatory ones. Seven years of marketing exclusivity, as a type of patent monopoly, is the most important relief that enables companies to make large profits. Conclusion. There are no sufficient funds and institutions to give financial support to the patients. It is therefore necessary to make health professionals much more aware of rare diseases in order to avoid time loss in making the right diagnosis and thus to gain more time to treat rare diseases. The importance of discovery, development and production of orphan drugs lies in the number of patients whose life quality can be improved significantly by administration of these drugs as well as in the number of potential survivals resulting from the treatment with these drugs. [Projekat Ministarstva nauke Republike Srbije, br. III 41012

  12. Study Drugs

    Science.gov (United States)

    ... messages back and forth by releasing chemicals called neurotransmitters. Prescription stimulants have chemical structures that are similar to some neurotransmitters. When someone takes them, the drugs boost the ...

  13. Electro-gene therapy in a human oral tongue cancer cell by intratumoral injection of pcDNA3.1-p27Kip1 wt

    Directory of Open Access Journals (Sweden)

    Supriatno Supriatno

    2007-03-01

    Full Text Available Oral tongue cancers are characterized by a high degree of local invasion and a high rate of metastases to the cervical lymph nodes. Also, treatment options for this cancer are limited. However, a new strategy for refractory cancer, gene therapy is watched with keen interest. Recently, a novel method for high-efficiency and region-controlled in vivo gene transfer was developed by combining in vivo electro-gene therapy and intratumoral plasmid DNA injection. In the present study, a nonviral gene transfer system, in vivo electrogene therapy in human oral tongue cancer cell, SP-C1 xenograft was examined. The aim of the study is to examine the efficiency of transfection of exogenous p27Kip1 gene by electroporation and the antitumor activity of p27Kip1 gene therapy in human oral tongue cancer xenografts using pcDNA3.1-p27Kip1 wild type (wt and pcDNA3.1 empty vector with the local application of electric pulses. To evaluate this in vivo gene transfer method, the enhanced green fluorescence protein (EGFP gene was transfected into xenografts by electroporation. The efficiency of transfection of exogenous p27Kip1 gene by electroporation was confirmed by Western blotting analysis. To estimate the reduction of oral tongue cancer xenografts by this method, the size of SP-C1 xenografts in nude mice after electroporation with wild type p27Kip1 gene was measured. The growth of tumors was markedly suppressed by wild type p27Kip1 gene transfection by electroporation compared with transfection of empty vector only. Moreover, histological specimens revealed apoptotic cell death was increased in wild type p27Kip1-transfected tumors than empty vector. These results suggest that it is possible to transfer wild type p27Kip1 into human oral tongue cancer xenografts using electroporation. Wild type p27Kip1 has a high-potencially to suppress the growth of tumors. Finally, combination system of pcDNA3.1-p27Kip1 wt-injected tumor and electroporationmight be used for human

  14. SU-C-210-04: Considerable Pancreatic Tumor Motion During Breath-Hold Measured Using Intratumoral Fiducials On Fluoroscopic Movies

    Energy Technology Data Exchange (ETDEWEB)

    Lens, E; Horst, A van der; Versteijne, E; Tienhoven, G van; Bel, A [Academic Medical Center, Amsterdam (Netherlands)

    2015-06-15

    Purpose: Using a breath hold (BH) technique during radiotherapy of pancreatic tumors is expected to reduce intra-fractional motion. The aim of this study was to evaluate the tumor motion during BH. Methods: In this pilot study, we included 8 consecutive pancreatic cancer patients. All had 2– 4 intratumoral gold fiducials. Patients were asked to perform 3 consecutive 30-second end-inhale BHs on day 5, 10 and 15 of their three-week treatment. During BH, airflow through a mouthpiece was measured using a spirometer. Any inadvertent flow of air during BH was monitored for all patients. We measured tumor motion on lateral fluoroscopic movies (57 in total) made during BH. In each movie the fiducials as a group were tracked over time in superior-inferior (SI) and anterior-posterior (AP) direction using 2-D image correlation between consecutive frames. We determined for each patient the range of intra-BH motion over all movies; we also determined the absolute means and standard deviations (SDs) for the entire patient group. Additionally, we investigated the relation between inadvertent airflow during BH and the intra-BH motion. Results: We found intra-BH tumor motion of up to 12.5 mm (range, 1.0–12.5 mm) in SI direction and up to 8.0 mm (range, 1.0–8.0 mm) in AP direction. The absolute mean motion over the patient population was 4.7 (SD: 3.0) mm and 2.8 (SD: 1.2) mm in the SI and AP direction, respectively. Patients were able to perform stable consecutive BHs; during only 20% of the movies we found very small airflows (≤ 65 ml). These were mostly stepwise in nature and could not explain the continuous tumor motions we observed. Conclusion: We found substantial (up to 12.5 mm) pancreatic tumor motion during BHs. We found minimal inadvertent airflow, seen only during a minority of BHs, and this did not explain the obtained results. This work was supported by the foundation Bergh in het Zadel through the Dutch Cancer Society (KWF Kankerbestrijding) project No. UVA 2011-5271.

  15. Drug Interactions

    Science.gov (United States)

    ... WITH HIV MEDICATIONS? Protease inhibitors and non-nucleoside reverse transcriptase inhibitors are processed by the liver and cause many ... taken with any protease inhibitor or non-nucleoside reverse transcriptase inhibitor. You can also check for drug-drug and ...

  16. Drug treatment

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    2010263 Drug resistance mechanism of non-small cell lung cancer PC9/AB2 cell line with acquired drug resistance to gefitinib.JU Lixia(鞠立霞),et al. Dept Oncol,Shanghai Pulm Hosp,Tongji Univ,Shanghai 200433. Chin J Tuberc Respir Dis 2010;33(5):354-358. Objective To

  17. Drugged Driving

    Science.gov (United States)

    ... in drivers measure the level of delta-9- tetrahydrocannabinol (THC), marijuana’s mind-altering ingredient, in the blood. But ... that marijuana plays in crashes is often unclear. THC can be detected in body fluids for days ...

  18. Drug treatment

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    2008227 Relationship between alterations of circulating cell-derived microparticles and glucocorticosteroid application.GAO Zengxin(高增鑫),et al.Dept Orthoped Surg,PUMC & CAMS,Beijing 100730.Natl Med J China 2008;88(15):1017-1021. Objective To explore the relationship between the alterations of circulating cell-derived microparticles(MPs)and large-dose glucocorticosteroid application.M

  19. Risk Alteration for Atrial Fibrillation with DifferentAntihypertensive Drugs

    Directory of Open Access Journals (Sweden)

    Vivencio Barrios, MD, PhD

    2011-12-01

    Full Text Available A large percentage of patients with hypertension suffer from atrial fibrillation (AF. The concomitance of both conditions in the same patient markedly increases cardiovascular risk. Therefore, prevention of new-onset AF in hypertensive population should be a relevant target. High blood pressure promotes structural and electrophysiological changes in the heart that promote the develop- ment of AF. Thus, the most important therapeutic approach to prevent incident AF in hypertensive population is to reduce blood pressure values to recommended goals. However, in specific conditions, some antihypertensive agents may provide additional benefits beyond blood pressure reduction, such as in hypertension with left ven- tricular hypertrophy with renin angiotensin system blockade. On the other hand, in patients with hypertension and permanent AF, beta blockers and nondihydropiridine calcium antagonists (verapamil and diltiazem play an important role. Antihypertensive agents may provide beneficial effects on incident AF, regardless of the presence of hyperten- sion. Thus, renin angiotensin system inhibitors may reduce new-onset AF in patients with heart failure or after the cardioversion of persistent AF. On the other hand, the preoperative administration of beta blockers may re- duce the incidence of postoperative AF in some patients. In this manuscript, the available evidence about the effects of different antihypertensive agents on new-onset AF in different populations is reviewed.

  20. Epigenomics and interindividual differences in drug response.

    Science.gov (United States)

    Ivanov, M; Kacevska, M; Ingelman-Sundberg, M

    2012-12-01

    Epigenomics is a rapidly growing field. New developments in epigenetics, such as the recently described modified cytosine variants (e.g., 5-hydroxymethylcytosine, 5hmC) and an arsenal of novel noncoding forms of RNA, can be applied in the area of drug pharmacokinetics and pharmacodynamics. Epigenetic aberrations can affect drug treatment by modulating the expressions of key genes involved in the metabolism and distribution of drugs as well as drug targets, thereby contributing to interindividual variation in drug response. These epigenetic alterations, along with the epigenetic profiles of circulating nucleic acids, have great potential to be used as biomarkers for personalized therapy, particularly in the treatment of cancer. In this review we present an update of pharmacoepigenetics with respect to epigenetic regulation of ADME genes (genes related to drug absorption, distribution, metabolism, and excretion) and drug targets, and we illustrate how this information can be used for predicting interindividual variations in drug response. PMID:23093317

  1. On the interaction between drugs of abuse and adolescent social behavior

    NARCIS (Netherlands)

    Trezza, V.; Baarendse, P.J.J.; Vanderschuren, L.J.M.J.

    2014-01-01

    Rationale Social factors influence drug abuse. Conversely, drugs of abuse alter social behavior. This is especially pertinent during post-weaning development, when there are profound changes in the social repertoire, and the sensitivity to the positive and negative effects of drugs of abuse is alter

  2. Drug Facts

    Medline Plus

    Full Text Available ... prescription drugs. The addiction slowly took over his life. I need different people around me. To stop ... marijuana, "Cristina" is making positive changes in her life. She finds support from family and friends who ...

  3. Drug Facts

    Medline Plus

    Full Text Available ... Websites Search Share Listen English Español Information about this page Click on the button that says "Listen" ... the computer will read the text to you. This web site talks about drug abuse, addiction and ...

  4. Drug Facts

    Medline Plus

    Full Text Available ... computer will read the text to you. This web site talks about drug abuse, addiction and treatment. ... of the U.S. Department of Health and Human Services . PDF documents require the free Adobe Reader . Microsoft ...

  5. Club Drugs

    Science.gov (United States)

    ... following information: Facts and Figures – Includes the latest information and statistics. Legislation – A sample of links to online Federal and ... recognized agencies and organizations that provide services or information. CLUB DRUGS Summary Facts & ... & Technical Assistance Grants & Funding Related ...

  6. COPD - control drugs

    Science.gov (United States)

    Chronic obstructive pulmonary disease - control drugs; Bronchodilators - COPD - control drugs; Beta agonist inhaler - COPD - control drugs; Anticholinergic inhaler - COPD - control drugs; Long-acting inhaler - COPD - ...

  7. Targeting molecular networks for drug research

    Directory of Open Access Journals (Sweden)

    José Pedro Pinto

    2014-06-01

    Full Text Available The study of molecular networks has recently moved into the limelight of biomedical research. While it has certainly provided us with plenty of new insights into cellular mechanisms, the challenge now is how to modify or even restructure these networks. This is especially true for human diseases, which can be regarded as manifestations of distorted states of molecular networks. Of the possible interventions for altering networks, the use of drugs is presently the most feasible. In this mini-review, we present and discuss some exemplary approaches of how analysis of molecular interaction networks can contribute to pharmacology (e.g., by identifying new drug targets or prediction of drug side effects, as well as listing pointers to relevant resources and software to guide future research. We also outline recent progress in the use of drugs for in vitro reprogramming of cells, which constitutes an example par excellence for altering molecular interaction networks with drugs.

  8. Nanodrug-enhanced radiofrequency tumor ablation: effect of micellar or liposomal carrier on drug delivery and treatment efficacy.

    Directory of Open Access Journals (Sweden)

    Marwan Moussa

    Full Text Available PURPOSE: To determine the effect of different drug-loaded nanocarriers (micelles and liposomes on delivery and treatment efficacy for radiofrequency ablation (RFA combined with nanodrugs. MATERIALS/METHODS: Fischer 344 rats were used (n = 196. First, single subcutaneous R3230 tumors or normal liver underwent RFA followed by immediate administration of i.v. fluorescent beads (20, 100, and 500 nm, with fluorescent intensity measured at 4-24 hr. Next, to study carrier type on drug efficiency, RFA was combined with micellar (20 nm or liposomal (100 nm preparations of doxorubicin (Dox; targeting HIF-1α or quercetin (Qu; targeting HSP70. Animals received RFA alone, RFA with Lipo-Dox or Mic-Dox (1 mg i.v., 15 min post-RFA, and RFA with Lipo-Qu or Mic-Qu given 24 hr pre- or 15 min post-RFA (0.3 mg i.v.. Tumor coagulation and HIF-1α or HSP70 expression were assessed 24 hr post-RFA. Third, the effect of RFA combined with i.v. Lipo-Dox, Mic-Dox, Lipo-Qu, or Mic-Qu (15 min post-RFA compared to RFA alone on tumor growth and animal endpoint survival was evaluated. Finally, drug uptake was compared between RFA/Lipo-Dox and RFA/Mic-Dox at 4-72 hr. RESULTS: Smaller 20 nm beads had greater deposition and deeper tissue penetration in both tumor (100 nm/500 nm and liver (100 nm (p<0.05. Mic-Dox and Mic-Qu suppressed periablational HIF-1α or HSP70 rim thickness more than liposomal preparations (p<0.05. RFA/Mic-Dox had greater early (4 hr intratumoral doxorubicin, but RFA/Lipo-Dox had progressively higher intratumoral doxorubicin at 24-72 hr post-RFA (p<0.04. No difference in tumor growth and survival was seen between RFA/Lipo-Qu and RFA/Mic-Qu. Yet, RFA/Lipo-Dox led to greater animal endpoint survival compared to RFA/Mic-Dox (p<0.03. CONCLUSION: With RF ablation, smaller particle micelles have superior penetration and more effective local molecular modulation. However, larger long-circulating liposomal carriers can result in greater intratumoral drug

  9. Herbal drugs and drug interactions

    Directory of Open Access Journals (Sweden)

    Gül Dülger

    2012-01-01

    Full Text Available Herbal drugs are defined as any form of a plant or plant product that contains a single herb or combinations of herbs that are believed to have complementary effects. Although they are considered to be safe, because they are natural, they may have various adverse effects, and may interact with other herbal products or conventional drugs. These interactions are especially important for drugs with narrow therapeutic indices.In the present study, pharmacokinetic and pharmacodynamic interactions of some most commanly used herbals (St John's wort, ginkgo biloba, ginseng, ginger, garlic, echinacea, ephedra and valerian with the conventional drugs were reviewed. Pharmacokinetic interactions involve mainly induction or inhibition of the cytochrome P450 isozymes and p-glycoproteins by the herbal medicine, thus changing the absorption and/or elimination rate and consequently the efficacy of the concommitantly used drugs. St John's wort, a well known enzyme inducer, decreases the efficacy of most of the other drugs that are known to be the substrates of these enzymes.Pharmacodynamic interactions may be due to additive or synergistic effects which results in enhanced effect or toxicity, or herbal medicines with antagonistic properties reduce drug efficacy and result in therapeutic failure. For exampla, St John's wort may have synergistic effects with other antidepressant drugs used by the patient, resulting in increased CNS effects.Herbals like ginseng, ginkgo, garlic, ginger were reported to increase bleeding time, thus potentiating the effect of anticoagulant and antithrombotic agents. In conclusion, patients should be warned against the interaction between the herbal products and conventional medicines.

  10. Abiraterone acetate: A novel drug for castration-resistant prostate carcinoma

    Directory of Open Access Journals (Sweden)

    R Nandha

    2012-01-01

    Full Text Available Androgen-deprivation therapy is the mainstay of treatment for the management of advanced prostate carcinoma till transition to castration-resistant prostate carcinoma (CRPC. Recently, adrenal and intratumoral synthesis of androgens has been found to be the major cause for CRPC. Abiraterone acetate is an orally active, potent and selective inhibitor of 17 a hydroxylase and c 17, 20 lyase, which acts by decreasing the de novo production of androgens with no rise in steroids downstream. Multiple randomized trials have shown significant improvement of >50% decline in prostate-specific antigen (PSA and time to PSA progression (TTPP with abiraterone acetate 1000 mg per day in chemotherapy/ketoconazole treated and naive CRPC patients producing reversible and manageable adverse effects due to mineralocorticoid excess. This article reviews the available evidence on efficacy and safety of this drug in CRPC. Searches of Pubmed, Cochrane database, Medscape, Google and clinicaltrial.org were made for terms like CRPC and abiraterone.

  11. Transungual drug delivery: current status.

    Science.gov (United States)

    Elkeeb, Rania; AliKhan, Ali; Elkeeb, Laila; Hui, Xiaoying; Maibach, Howard I

    2010-01-15

    Topical therapy is highly desirable in treating nail disorders due to its localized effects, which results in minimal adverse systemic events and possibly improved adherence. However, the effectiveness of topical therapies is limited by minimal drug permeability through the nail plate. Current research on nail permeation that focuses on altering the nail plate barrier by means of chemical treatments, penetration enhancers as well as physical and mechanical methods is reviewed. A new method of nail sampling is examined. Finally limitations of current ungual drug permeability studies are briefly discussed. PMID:19819318

  12. Transungual drug delivery: current status.

    Science.gov (United States)

    Elkeeb, Rania; AliKhan, Ali; Elkeeb, Laila; Hui, Xiaoying; Maibach, Howard I

    2010-01-15

    Topical therapy is highly desirable in treating nail disorders due to its localized effects, which results in minimal adverse systemic events and possibly improved adherence. However, the effectiveness of topical therapies is limited by minimal drug permeability through the nail plate. Current research on nail permeation that focuses on altering the nail plate barrier by means of chemical treatments, penetration enhancers as well as physical and mechanical methods is reviewed. A new method of nail sampling is examined. Finally limitations of current ungual drug permeability studies are briefly discussed.

  13. Legal Drugs Are Good Drugs And Illegal Drugs Are Bad Drugs

    OpenAIRE

    Dina Indrati; Herry Prasetyo

    2011-01-01

    ABSTRACT : Labelling drugs are important issue nowadays in a modern society. Although it is generally believed that legal drugs are good drugs and illegal drugs are bad drugs, it is evident that some people do not aware about the side effects of drugs used. Therefore, a key contention of this philosophical essay is that explores harms minimisation policy, discuss whether legal drugs are good drugs and illegal drugs are bad drugs and explores relation of drugs misuse in a psychiatric nursing s...

  14. Efficacy of the Oral Fluorouracil Pro-drug Capecitabine in Cancer Treatment: a Review

    Directory of Open Access Journals (Sweden)

    John Kouvaris

    2008-08-01

    Full Text Available Abstract: Capecitabine (Xeloda® was developed as a pro-drug of fluorouracil (FU, with the aim of improving tolerability and intratumor drug concentrations through its tumorspecific conversion to the active drug. The purpose of this paper is to review the available information on capecitabine, focusing on its clinical effectiveness against various carcinomas. Identification of all eligible English trails was made by searching the PubMed and Cochrane databases from 1980 to 2007. Search terms included capecitabine, Xeloda and cancer treatment. Nowadays, FDA has approved the use of capecitabine as a first line therapy in patients with metastatic colorectal cancer when single-agent fluoropyrimidine is preferred. The drug is also approved for use as a single agent in metastatic breast cancer patients who are resistant to both anthracycline and paclitaxel-based regimens or when further anthracycline treatment is contraindicated. It is also approved in combination with docetaxel after failure of prior anthracycline-based chemotherapy. In patients with prostate, pancreatic, renal cell and ovarian carcinomas, capecitabine as a single-agent or in combination with other drugs has also shown benefits. Improved tolerability and comparable efficacy, compared with the intravenous FU/LV combination, in addition to its oral administration, make capecitabine an attractive option for the treatment of several types of carcinomas.

  15. Neurobiological alterations in alcohol addiction: a review.

    Science.gov (United States)

    Erdozain, Amaia M; Callado, Luis F

    2014-01-01

    The exact mechanism by which ethanol exerts its effects on the brain is still unknown. However, nowadays it is well known that ethanol interacts with specific neuronal membrane proteins involved in signal transmission, resulting in changes in neural activity. In this review different neurochemical alterations produced by ethanol are described. Primarily, ethanol interacts with two membrane receptors: GABAA and NMDA ion channel receptors. Ethanol enhances the GABA action and antagonizes glutamate action, therefore acting as a CNS depressant. In addition, ethanol affects most other neurochemical and endocrine systems. In regard to the brain reward system, both dopaminergic and opioid system are affected by this drug. Furthermore, the serotonergic, noradrenergic, corticotropin-releasing factor and cannabinoid systems seem to play an important role in the neurobiology of alcoholism. At last but not least, ethanol can also modulate cytoplasmic components, including the second messengers. We also review briefly the different actual and putative pharmacological treatments for alcoholism, based on the alterations produced by this drug. PMID:25578004

  16. Drug Allergy.

    Science.gov (United States)

    Waheed, Abdul; Hill, Tiffany; Dhawan, Nidhi

    2016-09-01

    An adverse drug reaction relates to an undesired response to administration of a drug. Type A reactions are common and are predictable to administration, dose response, or interaction with other medications. Type B reactions are uncommon with occurrences that are not predictable. Appropriate diagnosis, classification, and entry into the chart are important to avoid future problems. The diagnosis is made with careful history, physical examination, and possibly allergy testing. It is recommended that help from allergy immunology specialists should be sought where necessary and that routine prescription of Epi pen should be given to patients with multiple allergy syndromes. PMID:27545730

  17. Drug effects on responses to emotional facial expressions: recent findings.

    Science.gov (United States)

    Miller, Melissa A; Bershad, Anya K; de Wit, Harriet

    2015-09-01

    Many psychoactive drugs increase social behavior and enhance social interactions, which may, in turn, increase their attractiveness to users. Although the psychological mechanisms by which drugs affect social behavior are not fully understood, there is some evidence that drugs alter the perception of emotions in others. Drugs can affect the ability to detect, attend to, and respond to emotional facial expressions, which in turn may influence their use in social settings. Either increased reactivity to positive expressions or decreased response to negative expressions may facilitate social interaction. This article reviews evidence that psychoactive drugs alter the processing of emotional facial expressions using subjective, behavioral, and physiological measures. The findings lay the groundwork for better understanding how drugs alter social processing and social behavior more generally. PMID:26226144

  18. Altered fingerprints: analysis and detection.

    Science.gov (United States)

    Yoon, Soweon; Feng, Jianjiang; Jain, Anil K

    2012-03-01

    The widespread deployment of Automated Fingerprint Identification Systems (AFIS) in law enforcement and border control applications has heightened the need for ensuring that these systems are not compromised. While several issues related to fingerprint system security have been investigated, including the use of fake fingerprints for masquerading identity, the problem of fingerprint alteration or obfuscation has received very little attention. Fingerprint obfuscation refers to the deliberate alteration of the fingerprint pattern by an individual for the purpose of masking his identity. Several cases of fingerprint obfuscation have been reported in the press. Fingerprint image quality assessment software (e.g., NFIQ) cannot always detect altered fingerprints since the implicit image quality due to alteration may not change significantly. The main contributions of this paper are: 1) compiling case studies of incidents where individuals were found to have altered their fingerprints for circumventing AFIS, 2) investigating the impact of fingerprint alteration on the accuracy of a commercial fingerprint matcher, 3) classifying the alterations into three major categories and suggesting possible countermeasures, 4) developing a technique to automatically detect altered fingerprints based on analyzing orientation field and minutiae distribution, and 5) evaluating the proposed technique and the NFIQ algorithm on a large database of altered fingerprints provided by a law enforcement agency. Experimental results show the feasibility of the proposed approach in detecting altered fingerprints and highlight the need to further pursue this problem. PMID:21808092

  19. Effects of Drug Abuse

    Science.gov (United States)

    ... Treatment Drug Treatment Facts Does Drug Treatment Work? Types of Drug Treatment What Is a Relapse? Find Treatment/Rehab Resources Friends and Family Can Help Prevent Drug Abuse Help Children and Teens Stay Drug-Free Talking ...

  20. Other Drugs of Abuse

    Science.gov (United States)

    ... Treatment Drug Treatment Facts Does Drug Treatment Work? Types of Drug Treatment What Is a Relapse? Find Treatment/Rehab Resources Friends and Family Can Help Prevent Drug Abuse Help Children and Teens Stay Drug-Free Talking ...

  1. Drug Facts

    Medline Plus

    Full Text Available ... Phone Numbers and Websites Search Share Listen English Español Information about this page Click on the button ... sobre el abuso de drogas, y adicción. English Español About the National Institute on Drug Abuse (NIDA) | ...

  2. Drug Facts

    Medline Plus

    Full Text Available ... Prevention Phone Numbers and Websites Search Share Listen English Español Information about this page Click on the ... información sobre el abuso de drogas, y adicción. English Español About the National Institute on Drug Abuse ( ...

  3. Drug Facts

    Medline Plus

    Full Text Available ... What Is a Relapse? Find Treatment/Rehab Resources Friends and Family Can Help Prevent Drug Abuse Help ... her life. She finds support from family and friends who don't use marijuana. Haga clic aquí ...

  4. Antineoplastic Drugs.

    Science.gov (United States)

    Morris, Sara; Michael, Nancy, Ed.

    This module on antineoplastic drugs is intended for use in inservice or continuing education programs for persons who administer medications in long-term care facilities. Instructor information, including teaching suggestions, and a listing of recommended audiovisual materials and their sources appear first. The module goal and objectives are then…

  5. Drugged Driving

    Science.gov (United States)

    ... View All NIDA's Publication Series Brain Power DrugFacts Mind Over Matter Research Reports NIDA Home Site Map FAQs Accessibility Privacy FOIA(NIH) Working at NIDA Contact Subscribe Archives PDF documents require the free Adobe Reader . Microsoft Word documents require the free Microsoft Word ...

  6. WOMEN AND DRUG ABUSE IN INDIA: CAUSES AND CONSEQUENCES

    OpenAIRE

    BIJAYALAXMI PANDA

    2013-01-01

    The social consequences, disadvantage and sub-ordination of women on the one hand, and the rapid socio-cultural and economic changes on the other have significantly altered traditional structures and institutions within society. Such changes are invariably associated with social upheaval, and drug abuse is a known outcome of such change. Clearly, drug abuse impacts women dually- male drug abuse creates enormous burden for the affected women, and drug abuser has even graver problems for women....

  7. Drug effects on responses to emotional facial expressions: recent findings

    OpenAIRE

    Miller, Melissa A.; Bershad, Anya K.; de Wit, Harriet

    2015-01-01

    Many psychoactive drugs increase social behavior and enhance social interactions, which may, in turn, increase their attractiveness to users. Although the psychological mechanisms by which drugs affect social behavior are not fully understood, there is some evidence that drugs alter the perception of emotions in others. Drugs can affect the ability to detect, attend to, and respond to emotional facial expressions, which in turn may influence their use in social settings. Either increased reac...

  8. Genetic Alterations in Glioma

    International Nuclear Information System (INIS)

    Gliomas are the most common type of primary brain tumor and have a dismal prognosis. Understanding the genetic alterations that drive glioma formation and progression may help improve patient prognosis by identification of novel treatment targets. Recently, two major studies have performed in-depth mutation analysis of glioblastomas (the most common and aggressive subtype of glioma). This systematic approach revealed three major pathways that are affected in glioblastomas: The receptor tyrosine kinase signaling pathway, the TP53 pathway and the pRB pathway. Apart from frequent mutations in the IDH1/2 gene, much less is known about the causal genetic changes of grade II and III (anaplastic) gliomas. Exceptions include TP53 mutations and fusion genes involving the BRAF gene in astrocytic and pilocytic glioma subtypes, respectively. In this review, we provide an update on all common events involved in the initiation and/or progression across the different subtypes of glioma and provide future directions for research into the genetic changes

  9. Music alters visual perception.

    Directory of Open Access Journals (Sweden)

    Jacob Jolij

    Full Text Available BACKGROUND: Visual perception is not a passive process: in order to efficiently process visual input, the brain actively uses previous knowledge (e.g., memory and expectations about what the world should look like. However, perception is not only influenced by previous knowledge. Especially the perception of emotional stimuli is influenced by the emotional state of the observer. In other words, how we perceive the world does not only depend on what we know of the world, but also by how we feel. In this study, we further investigated the relation between mood and perception. METHODS AND FINDINGS: We let observers do a difficult stimulus detection task, in which they had to detect schematic happy and sad faces embedded in noise. Mood was manipulated by means of music. We found that observers were more accurate in detecting faces congruent with their mood, corroborating earlier research. However, in trials in which no actual face was presented, observers made a significant number of false alarms. The content of these false alarms, or illusory percepts, was strongly influenced by the observers' mood. CONCLUSIONS: As illusory percepts are believed to reflect the content of internal representations that are employed by the brain during top-down processing of visual input, we conclude that top-down modulation of visual processing is not purely predictive in nature: mood, in this case manipulated by music, may also directly alter the way we perceive the world.

  10. Cutaneous adverse drug reactions caused by antituberculosis drugs.

    Science.gov (United States)

    Rezakovic, Saida; Pastar, Zrinjka; Kostovic, Kresimir

    2014-01-01

    Multidrug antituberculosis regimen is associated with diverse clinical patterns of cutaneous adverse drug reactions (CADR), ranging from mild and moderate such as pruritus, maculopapular exanthems, lichenoid eruptions, fixed drug eruptions and urticaria to severe and even life threatening ones like acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These adverse reactions to antituberculosis drugs are commonly observed adverse events. This is of particular importance for high HIV prevalence settings and developing countries where tuberculosis is common infection resulting in higher occurrence rate of these reactions. There is still significant heterogenity in definition and classification of CADR, as well as diversity in treatment modalities following adverse reactions and rechallenge management. The aim of this review is to discuss clinical presentation, occurrence of CADR caused by antituberculosis drugs, to identify risk factors for intolerance of the standard therapy as well as to draw attention to importance of multi-disciplinary approach, early detection, prompt diagnosis and in time management of antituberculosis drugs associated CADR. CADR can cause significant treatment interruption and alteration, resulting in increased risk of treatment failure, drug resistance, relapses and increased risk of complications including even lethal outcome. Finally, it can be concluded that it is of great importance to identify the best possible treatment and preventive regimens in order to enable continuity of the antituberculosis therapy to the full extent. PMID:25039910

  11. Chromatin regulation in drug addiction and depression

    OpenAIRE

    Renthal, William; Nestler, Eric J.

    2009-01-01

    Alterations in gene expression are implicated in the pathogenesis of several neuropsychiatrie disorders, including drug addiction and depression, increasing evidence indicates that changes in gene expression in neurons, in the context of animal models of addiction and depression, are mediated in part by epigenetic mechanisms that alter chromatin structure on specific gene promoters. This review discusses recent findings from behavioral, molecular, and bioinformatic approaches that are being u...

  12. A Drug Utilization Study of Psychotropic Drugs Prescribed in the Psychiatry Outpatient Department of a Tertiary Care Hospital

    OpenAIRE

    Thakkar, Karan B.; Jain, Mangal M.; Billa, Gauri; Joshi, Abhijit; Khobragade, Akash A.

    2013-01-01

    Background: Psychiatric disorders are one of the major causes of morbidity. Development of newer drugs like SSRIs and atypical antipsychotics has altered the treatment paradigms. Various factors like cost of drugs, local paradigms, etc. play a role in the selection of drug therapy and hence, affect the outcome. Keeping this in mind, we conducted a study to delineate the various drugs used in psychiatric disorders, to find discrepancies, if any, between the actual and the ideal prescribing pat...

  13. Estadios precoces de cancer oral: pronóstico en relación con gradación histológica, linfagiogénesis intratumoral y expresión de factor de crecimiento endotelial vascular Tipo-C (VEGF-C Early stage oral cancer: prognosis with regard to histological grading, intratumoral lymphangiogenesis, and the expression of vascular endothelial growth factor-C (VEGF-C

    Directory of Open Access Journals (Sweden)

    M.F. Muñoz-Guerra

    2006-02-01

    Full Text Available Objetivos. Los sistemas de gradación histológica se han usado clásicamente como factor pronóstico y marcadores de comportamiento clínico en el carcinoma epidermoide intra-oral (CEI. Sin embargo, su utilidad pronóstica permanece controvertida. Nuestro objetivo ha sido evaluar la presencia de linfangiogénesis intratumoral (LI, un nuevo hallazgo morfológico, en un análisis retrospectivo de muestras de tejido en parafina dentro de un grupo de estadios precoces de CEI, relacionándolo con clásicos sistemas de gradación histológica y teniendo en cuenta su importancia pronóstica. Asimismo, pretendemos determinar si la expresión del factor de crecimiento endotelial vascular -C (VEGF-C se correlaciona con la evolución de la enfermedad. Diseño. Realizamos un estudio retrospectivo basado en 96 casos de CEI. Todos los pacientes presentaban tumores intraorales T1-T2 y fueron tratados primariamente mediante resección local asociada con disección cervical electiva, la cual mostró ausencia de afectación ganglionar regional. En el grupo de 96 muestras analizamos la LI utilizando el marcador específico del endotelio linfático PA2.26. Adicionalmente, estudiamos la expresión del VEGF-C. Todos los casos fueron clasificados de acuerdo con los sistemas de gradación histológica descritos por Broders, Anneroth y Bryne. El estudio estadístico se fundamentó en el análisis univariante de supervivencia causa-específica y supervivencia libre de recidiva según el método de Kaplan-Meier. Resultados. El grupo de pacientes con ausencia de LI mostró mejor pronóstico en cuanto a supervivencia y periodo libre de enfermedad, aunque la diferencia no mostró valores estadísticamente significativos. El estudio no mostró una relación entre la expresión de VEGF-C y la presencia de LI. Sin embargo, no observamos recidivas entre el grupo con ausencia de expresión de VEGF-C. El análisis comparativo de los sistemas de gradación histológica mostró una

  14. Mephedrone alters basal ganglia and limbic dynorphin systems.

    Science.gov (United States)

    German, Christopher L; Alburges, Mario E; Hoonakker, Amanda J; Fleckenstein, Annette E; Hanson, Glen R

    2014-08-25

    Mephedrone (4-methymethcathinone) is a synthetic cathinone designer drug that disrupts central nervous system (CNS) dopamine (DA) signaling. Numerous central neuropeptide systems reciprocally interact with dopaminergic neurons to provide regulatory counterbalance, and are altered by aberrant DA activity associated with stimulant exposure. Endogenous opioid neuropeptides are highly concentrated within dopaminergic CNS regions and facilitate many rewarding and aversive properties associated with drug use. Dynorphin, an opioid neuropeptide and kappa receptor agonist, causes dysphoria and aversion to drug consumption through signaling within the basal ganglia and limbic systems, which is affected by stimulants. This study evaluated how mephedrone alters basal ganglia and limbic system dynorphin content, and the role of DA signaling in these changes. Repeated mephedrone administrations (4 × 25 mg/kg/injection, 2-h intervals) selectively increased dynorphin content throughout the dorsal striatum and globus pallidus, decreased dynorphin content within the frontal cortex, and did not alter dynorphin content within most limbic system structures. Pretreatment with D1 -like (SCH-23380) or D2 -like (eticlopride) antagonists blocked mephedrone-induced changes in dynorphin content in most regions examined, indicating altered dynorphin activity is a consequence of excessive DA signaling. Synapse, 2014. © 2014 Wiley Periodicals, Inc.

  15. Alcoholism, Drug Addiction, and the Road to Recovery: Life on the Edge.

    Science.gov (United States)

    Stimmel, Barry

    Originally published in 1992 as The Facts About Drug Use, this updated edition contains new information about the effects of alcohol and recreational, mood-altering drugs on the body. The multiple causes of drug use and the options available to those dependent on drugs as a way of life are thoroughly described. Knowledge of the adverse effects of…

  16. Neuroimmune Mechanisms of Alcohol and Drug Addiction

    OpenAIRE

    Cui, Changhai; Shurtleff, David; Harris, R. Adron

    2014-01-01

    Alcohol and other drugs of abuse have significant impacts on the neuroimmune system. Studies have demonstrated that drugs of abuse interact with the neuroimmune system and alter neuroimmune gene expression and signaling, which in turn contribute to various aspects of addiction. As the key component of the CNS immune system, neuroimmune factors mediate neuroinflammation and modulate a wide range of brain function including neuronal activity, endocrine function, and CNS development. These neuro...

  17. Single-cell analysis of targeted transcriptome predicts drug sensitivity of single cells within human myeloma tumors.

    Science.gov (United States)

    Mitra, A K; Mukherjee, U K; Harding, T; Jang, J S; Stessman, H; Li, Y; Abyzov, A; Jen, J; Kumar, S; Rajkumar, V; Van Ness, B

    2016-05-01

    Multiple myeloma (MM) is characterized by significant genetic diversity at subclonal levels that have a defining role in the heterogeneity of tumor progression, clinical aggressiveness and drug sensitivity. Although genome profiling studies have demonstrated heterogeneity in subclonal architecture that may ultimately lead to relapse, a gene expression-based prediction program that can identify, distinguish and quantify drug response in sub-populations within a bulk population of myeloma cells is lacking. In this study, we performed targeted transcriptome analysis on 528 pre-treatment single cells from 11 myeloma cell lines and 418 single cells from 8 drug-naïve MM patients, followed by intensive bioinformatics and statistical analysis for prediction of proteasome inhibitor sensitivity in individual cells. Using our previously reported drug response gene expression profile signature at the single-cell level, we developed an R Statistical analysis package available at https://github.com/bvnlabSCATTome, SCATTome (single-cell analysis of targeted transcriptome), that restructures the data obtained from Fluidigm single-cell quantitative real-time-PCR analysis run, filters missing data, performs scaling of filtered data, builds classification models and predicts drug response of individual cells based on targeted transcriptome using an assortment of machine learning methods. Application of SCATT should contribute to clinically relevant analysis of intratumor heterogeneity, and better inform drug choices based on subclonal cellular responses. PMID:26710886

  18. Altered systemic bioavailability and organ distribution of azathioprine in methotrexate-induced intestinal mucositis in rats

    Directory of Open Access Journals (Sweden)

    Sadaf A Karbelkar

    2016-01-01

    Conclusion: Study outcome has thrown light on altered fate of AZA when administered to individuals with mucositis which suggests modified drug therapy. These findings can further be investigated in different drug classes which might be administered concomitantly in mucositis and study outcome can be further confirmed in mucositis patients in clinical practice also.

  19. Drug Rash (Unclassified Drug Eruption) in Children

    Science.gov (United States)

    ... rash and rashes clinical tools newsletter | contact Share | Drug Eruption, Unclassified (Pediatric) A parent's guide to condition ... lesions coming together into larger lesions typical of drug rashes (eruptions). Overview A drug eruption, also known ...

  20. Perioperative dynamic alterations in peripheral regulatory T and B cells in patients with hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Chen Tianxiang

    2012-01-01

    Full Text Available Abstract Background Intratumoral and circulating regulatory T cells (Tregs have been shown to be critical in the pathogenesis of hepatocellular carcinoma (HCC. However there is limited knowledge on the alterations of regulatory B cells (Bregs. We here investigated perioperative dynamic alterations of peripheral circulating Tregs and Bregs in HCC patients to reveal the relationship between regulatory lymphocytes and its clinical implications. Methods 36 patients with HCC, 6 with chronic hepatitis B infection and 10 healthy donors were enrolled for this study. Frequencies of peripheral Tregs and Bregs were measured by flow cytometry with antibodies against CD4, CD25, CD127, CD19 and IL-10 before, and after radical surgery. Then, clinical informatics of HCC patients was achieved through Digital Evaluation Score System (DESS for the assessment of disease severity. Finally, we analysed correlations between digitalized clinical features and kinetics of circulating regulatory lymphocytes. Results Level of circulating CD4+CD25+CD127- Tregs in HCC patients was significantly lower than that in healthy donors and patients with chronic hepatitis B infection before surgery, but was increased after surgery. Preoperative level of CD19+ IL-10+ Bregs in HCC patients was also significantly lower than the other groups. However it dramatically was elevated right after surgery and remained elevated compared to controls (about 7 days after surgery, P = 0.04. Frequency of circulating Tregs was correlated with circulating leukocytes, ferritin, and clinical features suggesting tumor aggressiveness including portal vein thrombosis, hepatic vein involvement and advanced clinical stages. Frequency of circulating Bregs was associated with Hepatitis B e Antigen (HBeAg and Hepatitis B virus (HBV DNA copy number. In addition, DESS was significantly and positively correlated with other staging systems. Conclusion Frequencies of peripheral Tregs and Bregs in HCC patients

  1. Drug-Loaded Perfluorocarbon Nanodroplets for Ultrasound-Mediated Drug Delivery.

    Science.gov (United States)

    Rapoport, Natalya

    2016-01-01

    The interaction of nanoparticles with directed energy is a novel application in targeted drug delivery. This chapter focuses on perfluorocarbon nanoemulsions, whose action in drug delivery depends on the ultrasound-triggered phase shift from liquid to gaseous state. These nanoemulsions have great potential for unloading encapsulated drugs at a desired time and location in the body in response to directed ultrasound. In addition, they actively alter their nano-environment for enhancing drug transport through various biological barriers to sites of action, which significantly enhances therapeutic outcome.

  2. Gene expression profiling identifies microphthalmia-associated transcription factor (MITF and Dickkopf-1 (DKK1 as regulators of microenvironment-driven alterations in melanoma phenotype.

    Directory of Open Access Journals (Sweden)

    Mariusz L Hartman

    Full Text Available BACKGROUND: The diversity of functional phenotypes observed within a tumor does not exclusively result from intratumoral genetic heterogeneity but also from the response of cancer cells to the microenvironment. We have previously demonstrated that the morphological and functional phenotypes of melanoma can be dynamically altered upon external stimuli. FINDINGS: In the present study, transcriptome profiles were generated to explore the molecules governing phenotypes of melanospheres grown in the bFGF(+EGF(+ serum-free cultures and monolayers maintained in the serum-containing medium. Higher expression levels of MITF-dependent genes that are responsible for differentiation, e.g., TYR and MLANA, and stemness-related genes, e.g., ALDH1A1, were detected in melanospheres. These results were supported by the observation that the melanospheres contained more pigmented cells and cells exerting the self-renewal capacity than the monolayers. In addition, the expression of the anti-apoptotic, MITF-dependent genes e.g., BCL2A1 was also higher in the melanospheres. The enhanced activity of MITF in melanospheres, as illustrated by the increased expression of 74 MITF-dependent genes, identified MITF as a central transcriptional regulator in melanospheres. Importantly, several genes including MITF-dependent ones were expressed in melanospheres and original tumors at similar levels. The reduced MITF level in monolayers might be partially explained by suppression of the Wnt/β-catenin pathway, and DKK1, a secreted inhibitor of this pathway, was highly up-regulated in monolayers in comparison to melanospheres and original tumors. Furthermore, the silencing of DKK1 in monolayers increased the percentage of cells with self-renewing capacity. CONCLUSIONS: Our study indicates that melanospheres can be used to unravel the molecular pathways that sustain intratumoral phenotypic heterogeneity. Melanospheres directly derived from tumor specimens more accurately mirrored

  3. National Drug Code Directory

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Drug Listing Act of 1972 requires registered drug establishments to provide the Food and Drug Administration (FDA) with a current list of all drugs...

  4. Drugs Approved for Leukemia

    Science.gov (United States)

    This page lists cancer drugs approved by the FDA for use in leukemia. The drug names link to NCI's Cancer Drug Information summaries. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters.

  5. AIDSinfo Drug Database

    Science.gov (United States)

    ... Widgets Order Publications Skip Nav AIDS info Drug Database Home > Drugs Español small medium large Text Size ... health care providers and patients. Search the Drug Database Help × Search by drug name Performs a search ...

  6. Urine drug screen

    Science.gov (United States)

    Drug screen -- urine ... detect the presence of illegal and some prescription drugs in your urine. Their presence indicates that you recently used these drugs. Some drugs may remain in your system for ...

  7. Teenagers and drugs

    Science.gov (United States)

    ... and drugs; Symptoms of drug use in teenagers; Drug abuse - teenagers; Substance abuse - teenagers ... for a specialist who has experience working with teenagers. DO NOT ... drug abuse . You can find more information at teens.drugabuse. ...

  8. Drugs Approved for Retinoblastoma

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for retinoblastoma. The list includes generic names and brand names. The drug names link to NCI’s Cancer Drug Information summaries.

  9. Drugs Approved for Neuroblastoma

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for neuroblastoma. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  10. Managing antiepileptic drugs during pregnancy and lactation

    DEFF Research Database (Denmark)

    Sabers, Anne; Tomson, Torbjörn

    2009-01-01

    PURPOSE OF REVIEW: This review discusses data on the pharmacokinetics of antiepileptic drugs (AEDs) in pregnancy and lactation, and the clinical consequences thereof, thus providing a basis for a rational management of AEDs during pregnancy and lactation. RECENT FINDINGS: Studies have confirmed...... of AEDs in pregnancy and during lactation is important to enable optimal treatment. Gestation induced alterations in pharmacokinetics vary with the AED but also between patients and are difficult to predict. Therapeutic drug monitoring is, therefore, advisable during pregnancy and the use...... of the individual patient's optimal prepregnancy drug level is recommended as reference. Breastfeeding is in general safe but needs appropriate observation of the nursing infant....

  11. Epigenetic alterations in gastric carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    In-Seon CHOI; Tsung-Teh WU

    2005-01-01

    Gastric cancer is believed to result in part from the accumulation of multiple genetic alterations leading to oncogene overexpression and tumor suppressor loss. Epigenetic alterations as a distinct and crucial mechanism to silence a variety of methylated tissue-specific and imprinted genes, have been extensively studied in gastric carcinoma and play important roles in gastric carcinogenesis. This review will briefly discuss the basic aspects of DNA methylation and CpG island methylation, in particular the epigenetic alterations of certain critical genes implicated in gastric carcinogenesis and its relevance of clinical implications.

  12. CONCEPT OF DRUG INTERACTION

    OpenAIRE

    Singh Nidhi

    2012-01-01

    Drug interaction is an increasingly important cause of adverse reactions (ADR), and is the modification of the effect of one drug (object) by the prior or concomitant administration of another drug (precipitant drug). Drug interaction may either enhance or diminish the intended effect of one or both drugs. For example severe haemorrhage may occur if warfarin and salicylates (asprin) are combined. Precipitant drugs modify the object drug's absorption, distribution, metabolism, excretion or act...

  13. Dipeptidylpeptidase-4 inhibitors (gliptins): focus on drug-drug interactions.

    Science.gov (United States)

    Scheen, André J

    2010-09-01

    speaking, almost no drug-drug interactions or only minor drug-drug interactions have been reported between DPP-4 inhibitors and any of these drugs. The gliptins do not significantly modify the pharmacokinetic profile and exposure of the other tested drugs, and the other drugs do not significantly alter the pharmacokinetic profile of the gliptins or exposure to these. The only exception concerns saxagliptin, which is metabolized to an active metabolite by CYP3A4/5. Therefore, exposure to saxagliptin and its primary metabolite may be significantly modified when saxagliptin is coadministered with specific strong inhibitors (ketoconazole, diltiazem) or inducers (rifampicin) of CYP3A4/5 isoforms. The absence of significant drug-drug interactions could be explained by the favourable pharmacokinetic characteristics of DPP-4 inhibitors, which are not inducers or inhibitors of CYP isoforms and are not bound to plasma proteins to a great extent. Therefore, according to these pharmacokinetic findings, which were generally obtained in healthy young male subjects, no dosage adjustment is recommended when gliptins are combined with other pharmacological agents in patients with T2DM, with the exception of a reduction in the daily dosage of saxagliptin when this drug is used in association with a strong inhibitor of CYP3A4/A5. It is worth noting, however, that a reduction in the dose of sulfonylureas is usually recommended when a DPP-4 inhibitor is added, because of a pharmacodynamic interaction (rather than a pharmacokinetic interaction) between the sulfonylurea and the DPP-4 inhibitor, which may result in a higher risk of hypoglycaemia. Otherwise, any gliptin may be combined with metformin or a thiazolidinedione (pioglitazone, rosiglitazone), leading to a significant improvement in glycaemic control without an increased risk of hypoglycaemia or any other adverse event in patients with T2DM. Finally, the absence of drug-drug interactions in clinical trials in healthy subjects requires

  14. Pulmonary alterations in Behcet's disease

    International Nuclear Information System (INIS)

    Purpose: This study aims to demonstrate pulmonary alterations (PA) in patients with Behcet's disease by using CT. Materials and methods: CTs of 50 patients with Behcet's disease and 20 others in a control group have been evaluated retrospectively for PA (septal, reticular, nodular, atelectatic opacities). Results: Eight out of 50 patients (16%) with Behcet's disease showed PA. Three out of 20 (15%) in the control group showed PA. No differences were observed between Behcet's disease patients and the control group regarding pulmonary alterations (p = 0.917). No differences were observed in the disease duration, ages and sex in either group in those with and without PA. Conclusion: Pulmonary alterations can be seen in patients with Behcet's disease, but these alterations are not significant.

  15. Altered membrane lipid dynamics and chemoprevention by non-steroidal anti inflammatory drugs during colon carcinogenesis Alteración de la dinámica de los lípidos de membrana y quimioprevención mediante los fármacos antiinflamatorios no esteroideos en la carcinogénesis de colon

    Directory of Open Access Journals (Sweden)

    S. Singh Kanwar

    2011-10-01

    Full Text Available The present work focuses on the anti-neoplastic role of non steroidal anti-inflammatory drugs (NSAIDs in modulating the biophysical parameters of the colonic membranes in 1,2-dimethylhydrazine dihydrochloride (DMH induced carcinogenesis. The steady-state fluorescence polarization technique was applied to assess membrane fluidity, membrane polarity and lipid phase states. The decline in cholesterol content, biosynthesis and cholesterol: phospholipids ratio with DMH treatment indicates more fluidity associated with carcinogenesis. The DMH group had shown lower order parameter indicating more fluidity whereas NSAIDs resulted in increasing the membrane lipid order. The converging effects of these changes were more in membrane phase separations and membrane phase state. In DMH treatment membrane shows lesser phase separation or high polarity, and more liquid crystalline state while for NSAID groups membranes have higher phase separations or low polarity, and more of the gel phase. Further, NSAIDs induced anti-proliferative effects were evidently observed by apoptosis in the colonocytes by using acridine orange-ethidium bromide fluorescent staining and Terminal de-oxynucleotidyl transferase dUTP nick end labeling (TUNEL assay. The results suggest that NSAIDs induced alteration in the membrane biophysical parameters may be an important initiating event for the chemopreventive action.Este trabajo se centra en el papel antineoplásico de los fármacos antiinflamatorios no esteroideos (AINE en la modulación de los parámetros biofísicos de las membranas colónicas en la carcinogénesis inducida por 1,2-dihidrocloruro de dimetilhidracina (DMH. Se aplicó la técnica de polarización de la fluorescencia en estado de equilibrio para evaluar la fluidez de la membrana, su polaridad y los estados de fase lipídica. El declive del contenido de colesterol, la biosíntesis y el cociente colesterol: fosfolípidos con el tratamiento con DMH indica más fluidez

  16. Polymer-Based Prodrugs: Improving Tumor Targeting and the Solubility of Small Molecule Drugs in Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Sonja Dragojevic

    2015-12-01

    Full Text Available The majority of anticancer drugs have poor aqueous solubility, produce adverse effects in healthy tissue, and thus impose major limitations on both clinical efficacy and therapeutic safety of cancer chemotherapy. To help circumvent problems associated with solubility, most cancer drugs are now formulated with co-solubilizers. However, these agents often also introduce severe side effects, thereby restricting effective treatment and patient quality of life. A promising approach to addressing problems in anticancer drug solubility and selectivity is their conjugation with polymeric carriers to form polymer-based prodrugs. These polymer-based prodrugs are macromolecular carriers, designed to increase the aqueous solubility of antitumor drugs, can enhance bioavailability. Additionally, polymer-based prodrugs approach exploits unique features of tumor physiology to passively facilitate intratumoral accumulation, and so improve chemodrug pharmacokinetics and pharmacological properties. This review introduces basic concepts of polymer-based prodrugs, provides an overview of currently emerging synthetic, natural, and genetically engineered polymers that now deliver anticancer drugs in preclinical or clinical trials, and highlights their major anticipated applications in anticancer therapies.

  17. Polymer-Based Prodrugs: Improving Tumor Targeting and the Solubility of Small Molecule Drugs in Cancer Therapy.

    Science.gov (United States)

    Dragojevic, Sonja; Ryu, Jung Su; Raucher, Drazen

    2015-12-04

    The majority of anticancer drugs have poor aqueous solubility, produce adverse effects in healthy tissue, and thus impose major limitations on both clinical efficacy and therapeutic safety of cancer chemotherapy. To help circumvent problems associated with solubility, most cancer drugs are now formulated with co-solubilizers. However, these agents often also introduce severe side effects, thereby restricting effective treatment and patient quality of life. A promising approach to addressing problems in anticancer drug solubility and selectivity is their conjugation with polymeric carriers to form polymer-based prodrugs. These polymer-based prodrugs are macromolecular carriers, designed to increase the aqueous solubility of antitumor drugs, can enhance bioavailability. Additionally, polymer-based prodrugs approach exploits unique features of tumor physiology to passively facilitate intratumoral accumulation, and so improve chemodrug pharmacokinetics and pharmacological properties. This review introduces basic concepts of polymer-based prodrugs, provides an overview of currently emerging synthetic, natural, and genetically engineered polymers that now deliver anticancer drugs in preclinical or clinical trials, and highlights their major anticipated applications in anticancer therapies.

  18. Phase I/IIa study of intratumoral/intracerebral or intravenous/intracerebral administration of Parvovirus H-1 (ParvOryx in patients with progressive primary or recurrent glioblastoma multiforme: ParvOryx01 protocol

    Directory of Open Access Journals (Sweden)

    Geletneky Karsten

    2012-03-01

    Full Text Available Abstract Background The treatment of patients with malignant brain tumors remains a major oncological problem. The median survival of patients with glioblastoma multiforme (GBM, the most malignant type, is only 15 months after initial diagnosis and even less after tumor recurrence. Improvements of standard treatment including surgery and radio-chemotherapy have not lead to major improvements. Therefore, alternative therapeutics such as oncolytic viruses that specifically target and destroy cancer cells are under investigation. Preclinical data of oncolytic parvovirus H-1 (H-1PV infection of glioma cells demonstrated strong cytotoxic and oncosuppressing effects, leading to a phase I/IIa trial of H-1PV in patients with recurrent GBM (ParvOryx01. ParvOryx01 is the first trial with a replication competent oncolytic virus in Germany. Methods ParvOryx01 is an open, non-controlled, two groups, intra-group dose escalation, single center, phase I/IIa trial. 18 patients with recurrent GBM will be treated in 2 groups of 9 patients each. Treatment group 1 will first receive H-1PV by intratumoral injection and second by administration into the walls of the tumor cavity during tumor resection. In treatment group 2 the virus will initially be injected intravenously and afterwards, identical to group 1, into the surrounding brain tissue during tumor removal. Main eligibility criteria are: age of 18 years, unifocal recurrent GBM, amenable to complete or subtotal resection. Dose escalation will be based on the Continual Reassessment Method. The primary objective of the trial is local and systemic safety and tolerability and to determine the maximum tolerated dose (MTD. Secondary objectives are proof of concept (PoC and Progression-free Survival (PFS up to 6 months. Discussion This is the first trial with H-1PV in patients with recurrent GBM. The risks for the participants appear well predictable and justified. Furthermore, ParvOryx01 will be the first assessment

  19. Phase I/IIa study of intratumoral/intracerebral or intravenous/intracerebral administration of Parvovirus H-1 (ParvOryx) in patients with progressive primary or recurrent glioblastoma multiforme: ParvOryx01 protocol

    International Nuclear Information System (INIS)

    The treatment of patients with malignant brain tumors remains a major oncological problem. The median survival of patients with glioblastoma multiforme (GBM), the most malignant type, is only 15 months after initial diagnosis and even less after tumor recurrence. Improvements of standard treatment including surgery and radio-chemotherapy have not lead to major improvements. Therefore, alternative therapeutics such as oncolytic viruses that specifically target and destroy cancer cells are under investigation. Preclinical data of oncolytic parvovirus H-1 (H-1PV) infection of glioma cells demonstrated strong cytotoxic and oncosuppressing effects, leading to a phase I/IIa trial of H-1PV in patients with recurrent GBM (ParvOryx01). ParvOryx01 is the first trial with a replication competent oncolytic virus in Germany. ParvOryx01 is an open, non-controlled, two groups, intra-group dose escalation, single center, phase I/IIa trial. 18 patients with recurrent GBM will be treated in 2 groups of 9 patients each. Treatment group 1 will first receive H-1PV by intratumoral injection and second by administration into the walls of the tumor cavity during tumor resection. In treatment group 2 the virus will initially be injected intravenously and afterwards, identical to group 1, into the surrounding brain tissue during tumor removal. Main eligibility criteria are: age of 18 years, unifocal recurrent GBM, amenable to complete or subtotal resection. Dose escalation will be based on the Continual Reassessment Method. The primary objective of the trial is local and systemic safety and tolerability and to determine the maximum tolerated dose (MTD). Secondary objectives are proof of concept (PoC) and Progression-free Survival (PFS) up to 6 months. This is the first trial with H-1PV in patients with recurrent GBM. The risks for the participants appear well predictable and justified. Furthermore, ParvOryx01 will be the first assessment of combined intratumoral and intravenous application

  20. Drug abuse

    International Nuclear Information System (INIS)

    This paper reports that this study used SPECT to examine patients who have abused drugs to determine whether SPECT could identify abnormalities and whether these findings have clinical importance. Fifteen patients with a history of substance abuse (eight with cocaine, six with amphetamine, and one with organic solvent) underwent SPECT performed with a triple-headed camera and Tc-99m HMPAO both early for blood flow and later for functional information. These images were then processed into a 3D videotaped display used in group therapy. All 15 patients had multiple areas of decreased tracer uptake peppered throughout the cortex but mainly affecting the parietal lobes, expect for the organic solvent abuser who had a large parietal defect. The videotapes were subjectively described by a therapist as an exceptional tool that countered patient denial of physical damage from substance abuse. Statistical studies of recidivism between groups is under way

  1. Drug-drug interactions in the hospital

    OpenAIRE

    Vonbach, Priska

    2007-01-01

    Introduction Drug interaction screening programs are an important tool to check prescriptions of multiple drugs for potential drug-drug interactions (pDDIs). Several programs are available on the market. They differ in layout, update frequency, search functions, content and price. The aim of the current study was to critically appraise several interaction screening programs in the Department of Medicine of a Swiss public teaching hospital. Methods A drug interaction screening program had to f...

  2. [Drug-drug interactions in the elderly : Which ones really matter?].

    Science.gov (United States)

    Bitter, K; Schlender, J F; Woltersdorf, R

    2016-07-01

    Pharmacotherapy in the elderly is challenging due to age-related physiological changes, high interindividual variability, and increasing frequency of multimorbidity. The resulting polypharmacy increases the risk of drug-drug interactions and requires an individual risk assessment. Some drug-drug interactions are documented to be associated with harm in older adults including intoxication, gastrointestinal bleeding, or falls. Therefore, they are considered to be of special importance in the elderly. Moreover, frequent risk factors and continuous physiological alterations in the elderly should be taken into account during risk assessment. This review exemplifies clinically relevant drug-drug interactions and risk factors in the elderly. In addition, assessment tools as well as prevention and management strategies for clinical practice are presented. PMID:27294383

  3. Striatal Signal Transduction and Drug Addiction

    Science.gov (United States)

    Philibin, Scott D.; Hernandez, Adan; Self, David W.; Bibb, James A.

    2011-01-01

    Drug addiction is a severe neuropsychiatric disorder characterized by loss of control over motivated behavior. The need for effective treatments mandates a greater understanding of the causes and identification of new therapeutic targets for drug development. Drugs of abuse subjugate normal reward-related behavior to uncontrollable drug-seeking and -taking. Contributions of brain reward circuitry are being mapped with increasing precision. The role of synaptic plasticity in addiction and underlying molecular mechanisms contributing to the formation of the addicted state are being delineated. Thus we may now consider the role of striatal signal transduction in addiction from a more integrative neurobiological perspective. Drugs of abuse alter dopaminergic and glutamatergic neurotransmission in medium spiny neurons of the striatum. Dopamine receptors important for reward serve as principle targets of drugs abuse, which interact with glutamate receptor signaling critical for reward learning. Complex networks of intracellular signal transduction mechanisms underlying these receptors are strongly stimulated by addictive drugs. Through these mechanisms, repeated drug exposure alters functional and structural neuroplasticity, resulting in transition to the addicted biological state and behavioral outcomes that typify addiction. Ca2+ and cAMP represent key second messengers that initiate signaling cascades, which regulate synaptic strength and neuronal excitability. Protein phosphorylation and dephosphorylation are fundamental mechanisms underlying synaptic plasticity that are dysregulated by drugs of abuse. Increased understanding of the regulatory mechanisms by which protein kinases and phosphatases exert their effects during normal reward learning and the addiction process may lead to novel targets and pharmacotherapeutics with increased efficacy in promoting abstinence and decreased side effects, such as interference with natural reward, for drug addiction. PMID

  4. Nanoparticle tumor localization, disruption of autophagosomal trafficking, and prolonged drug delivery improve survival in peritoneal mesothelioma.

    Science.gov (United States)

    Liu, Rong; Colby, Aaron H; Gilmore, Denis; Schulz, Morgan; Zeng, Jialiu; Padera, Robert F; Shirihai, Orian; Grinstaff, Mark W; Colson, Yolonda L

    2016-09-01

    The treatment outcomes for malignant peritoneal mesothelioma are poor and associated with high co-morbidities due to suboptimal drug delivery. Thus, there is an unmet need for new approaches that concentrate drug at the tumor for a prolonged period of time yielding enhanced antitumor efficacy and improved metrics of treatment success. A paclitaxel-loaded pH-responsive expansile nanoparticle (PTX-eNP) system is described that addresses two unique challenges to improve the outcomes for peritoneal mesothelioma. First, following intraperitoneal administration, eNPs rapidly and specifically localize to tumors. The rate of eNP uptake by tumors is an order of magnitude faster than the rate of uptake in non-malignant cells; and, subsequent accumulation in autophagosomes and disruption of autophagosomal trafficking leads to prolonged intracellular retention of eNPs. The net effect of these combined mechanisms manifests as rapid localization to intraperitoneal tumors within 4 h of injection and persistent intratumoral retention for >14 days. Second, the high tumor-specificity of PTX-eNPs leads to delivery of greater than 100 times higher concentrations of drug in tumors compared to PTX alone and this is maintained for at least seven days following administration. As a result, overall survival of animals with established mesothelioma more than doubled when animals were treated with multiple doses of PTX-eNPs compared to equivalent dosing with PTX or non-responsive PTX-loaded nanoparticles. PMID:27343465

  5. The changing landscape of antiparasitic drug discovery for veterinary medicine.

    Science.gov (United States)

    Geary, Timothy G; Conder, George A; Bishop, Bernard

    2004-10-01

    Changes in economic imperatives in the pharmaceutical industry have led to a wave of consolidation, which has had the unintended side effect of shrinking the resource devoted to antiparasitic drug discovery in animal health companies. Scientific changes have altered the way in which drugs could be discovered in the future. New science and business models will need to be implemented to address the demand for innovative antiparasitic drugs in veterinary medicine. Novel drugs are needed to combat drug resistance and for currently non-addressed problems. At the center of the future for this field, however, lies the need for more support into the basic research on the biology of parasites. PMID:15363437

  6. Hallucinogens and Dissociative Drugs, Including LSD, PCP, Ketamine, Dextromethorphan. National Institute on Drug Abuse Research Report Series.

    Science.gov (United States)

    National Inst. on Drug Abuse (DHHS/PHS), Rockville, MD.

    Research is developing a clearer picture of the dangers of mind-altering drugs. The goal of this report is to present the latest information to providers to help them strengthen their prevention and treatment efforts. A description is presented of dissociative drugs, and consideration is given as to why people take hallucinogens. The physical…

  7. Perfluorocarbon (PFC) emulsions as potential drug carriers

    International Nuclear Information System (INIS)

    PFC emulsions have excellent oxygen transporting properties and have been reported to enhance the response of murine tumors to both radiation and BCNU. While the presently available emulsions are far too toxic to the immune system to be used in cancer therapy, they can be used to investigate the overall potential of this approach. As an example, the authors have found that these emulsions can alter drug availability. The lipophilicity of both the PFC and the drug in question determine the partitioning of the drug between the organic and aqueous phases of an emulsion. In vitro, this can reduce drug effectiveness by reducing the amount of drug available to the cells. In vivo, however, this partitioning may produce sustained drug exposure, which could be of benefit in cancer therapy and other applications. In brief, as the drug is absorbed from the circulating aqueous phase, additional drug would leach from the PFC, thereby providing a sustained drug exposure similar to that obtained with liposomes. While a great deal more work will be required to evaluate the practicality of this approach, the existence of this phenomenon must be taken into account in both the design and interpretation of efficacy studies in which anesthetics, chemotherapeutics, etc are employed

  8. Personality, Drug Preference, Drug Use, and Drug Availability

    Science.gov (United States)

    Feldman, Marc; Boyer, Bret; Kumar, V. K.; Prout, Maurice

    2011-01-01

    This study examined the relationship between drug preference, drug use, drug availability, and personality among individuals (n = 100) in treatment for substance abuse in an effort to replicate the results of an earlier study (Feldman, Kumar, Angelini, Pekala, & Porter, 2007) designed to test prediction derived from Eysenck's (1957, 1967)…

  9. Drug-interactions of azole antifungals with selected immunosuppressants in transplant patients: strategies for optimal management in clinical practice

    NARCIS (Netherlands)

    Lempers, V.J.C.; Martial, L.C.; Schreuder, M.F.; Blijlevens, N.M.A.; Burger, D.M.; Aarnoutse, R.E.; Bruggemann, R.J.M.

    2015-01-01

    The management of drug-drug interactions (DDIs) between azole antifungals (fluconazole, itraconazole, posaconazole and voriconazole) and immunosuppressants (cyclosporine, tacrolimus, everolimus and sirolimus) in transplant patients remains challenging, as the impact of altered immunosuppressant conc

  10. Systemic CD8+ T cell-mediated tumoricidal effects by intratumoral treatment of oncolytic herpes simplex virus with the agonistic monoclonal antibody for murine glucocorticoid-induced tumor necrosis factor receptor.

    Directory of Open Access Journals (Sweden)

    Mikiya Ishihara

    Full Text Available Oncolytic virotherapy combined with immunomodulators is a novel noninvasive strategy for cancer treatment. In this study, we examined the tumoricidal effects of oncolytic HF10, a naturally occurring mutant of herpes simplex virus type-1, combined with an agonistic DTA-1 monoclonal antibody specific for the glucocorticoid-induced tumor necrosis factor receptor. Two murine tumor models were used to evaluate the therapeutic efficacies of HF10 virotherapy combined with DTA-1. The kinetics and immunological mechanisms of DTA-1 in HF10 infection were examined using flow cytometry and immunohistochemistry. Intratumoral administration of HF10 in combination with DTA-1 at a low dose resulted in a more vigorous attenuation of growth of the untreated contralateral as well as the treated tumors than treatment with either HF10 or DTA-1 alone. An accumulation of CD8(+ T cells, including tumor- and herpes simplex virus type-1-specific populations, and a decrease in the number of CD4(+ Foxp3(+ T regulatory cells were seen in both HF10- and DTA-1-treated tumors. Studies using Fc-digested DTA-1 and Fcγ receptor knockout mice demonstrated the direct participation of DTA-1 in regulatory T cell depletion by antibody-dependent cellular cytotoxicity primarily via macrophages. These results indicated the potential therapeutic efficacy of a glucocorticoid-induced tumor necrosis factor receptor-specific monoclonal antibody in oncolytic virotherapy at local tumor sites.

  11. Developing a Molecular Roadmap of Drug-Food Interactions

    DEFF Research Database (Denmark)

    Jensen, Kasper; Ni, Yueqiong; Panagiotou, Gianni;

    2015-01-01

    Recent research has demonstrated that consumption of food -especially fruits and vegetables-can alter the effects of drugs by interfering either with their pharmacokinetic or pharmacodynamic processes. Despite the recognition of such drug-food associations as an important element for successful...... view of the associations between diet and dietary molecules with drug targets, metabolic enzymes, drug transporters and carriers currently deposited in Drug-Bank. Moreover, we identified disease areas and drug targets that are most prone to the negative effects of drug-food interactions, showcasing...... therapeutic interventions, a systematic approach for identifying, predicting and preventing potential interactions between food and marketed or novel drugs is not yet available. The overall objective of this work was to sketch a comprehensive picture of the interference of ∼ 4,000 dietary components present...

  12. Drugs and lactation

    International Nuclear Information System (INIS)

    Different kinds of drugs who can be transferred through the mother's milk to the lactant and its effects are showed in this work. A list of them as below: cardiotonics, diuretics, anti-hypertensives, beta-blockings, anti-arrythmics, drugs with gastrintestinal tract action, hormones, antibiotics and chemotherapeutics, citostatic drugs, central nervous system action drugs and anticoagulants drugs. (L.M.J.)

  13. Long non-coding RNAs in cancer drug resistance development.

    Science.gov (United States)

    Majidinia, Maryam; Yousefi, Bahman

    2016-09-01

    The presence or emergence of chemoresistance in tumor cells is a major burden in cancer therapy. While drug resistance is a multifactorial phenomenon arising from altered membrane transport of drugs, altered drug metabolism, altered DNA repair, reduced apoptosis rate and alterations of drug metabolism, it can also be linked to genetic and epigenetic factors. Long non-coding RNAs (lncRNAs) have important regulatory roles in many aspects of genome function including gene transcription, splicing, and epigenetics as well as biological processes involved in cell cycle, cell differentiation, development, and pluripotency. As such, it may not be surprising that some lncRNAs have been recently linked to carcinogenesis and drug resistance/sensitivity. Research is accelerating to decipher the exact molecular mechanism of lncRNA-regulated drug resistance and its therapeutic implications. In this article, we will review the structure, biogenesis, and mode of action of lncRNAs. Then, the involvement of lncRNAs in drug resistance will be discussed in detail. PMID:27427176

  14. [Drug-drug interactions in antirheumatic treatment].

    Science.gov (United States)

    Krüger, K

    2012-04-01

    Clinically relevant drug-drug interactions contribute considerably to potentially dangerous drug side-effects and are frequently the reason for hospitalization. Nevertheless they are often overlooked in daily practice. For most antirheumatic drugs a vast number of interactions have been described but only a minority with clinical relevance. Several potentially important drug interactions exist for non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate, azathioprine, mycophenolate-mofetil and especially for cyclosporin A. Most importantly co-medication with methotrexate and sulfmethoxazole trimethoprim as well as azathioprine and allopurinol carries the risk of severe, sometimes life-threatening consequences. Nevertheless, besides these well-known high-risk combinations in each case of polypharmacy with antirheumatic drugs it is necessary to bear in mind the possibility of drug interactions. As polypharmacy is a common therapeutic practice in older patients with rheumatic diseases, they are at special risk. PMID:22527215

  15. First In Vivo Testing of Compounds Targeting Group 3 Medulloblastomas Using an Implantable Microdevice as a New Paradigm for Drug Development.

    Science.gov (United States)

    Jonas, Oliver; Calligaris, David; Methuku, Kashi Reddy; Poe, Michael M; Francois, Jessica Pierre; Tranghese, Frank; Changelian, Armen; Sieghart, Werner; Ernst, Margot; Krummel, Daniel A Pomeranz; Cook, James M; Pomeroy, Scott L; Cima, Michael; Agar, Nathalie Y R; Langer, Robert; Sengupta, Soma

    2016-06-01

    Medulloblastoma is the most common childhood malignant brain tumor. The most lethal medulloblastoma subtype exhibits a high expression of the GABAA receptor α5 subunit gene and MYC amplification. New benzodiazepines have been synthesized to function as α5-GABAA receptor ligands. To compare their efficacy with that of standard-of-care treatments, we have employed a newly developed microscale implantable device that allows for high-throughput localized intratumor drug delivery and efficacy testing. Microdoses of each drug were delivered into small distinct regions of tumors, as confirmed by tissue mass spectrometry, and the local drug effect was determined by immunohistochemistry. We have identified a benzodiazepine derivative, KRM-II-08, as a new potent inhibitor in several α5-GABAA receptor expressing tumor models. This is the first instance of in vivo testing of several benzodiazepine derivatives and standard chemotherapeutic drugs within the same tumor. Obtaining high-throughput drug efficacy data within a native tumor microenvironment as detailed herein, prior to pharmacological optimization for bioavailability or safety and without systemic exposure or toxicity, may allow for rapid prioritization of drug candidates for further pharmacological optimization. PMID:27319222

  16. Drugs and drug policy in the Netherlands

    OpenAIRE

    Leuw, Ed.

    1991-01-01

    The Dutch parliament enacted the revised Opium Act in 1976. This penal law is part of the Dutch drug policy framework that includes tolerance for nonconforming lifestyles, risk reduction in regard to the harmful health and social consequences of drug taking, and penal measures directed against illegal trafficking in hard drugs. This multifaceted approach established the basic principles and operating practices of contemporary social and criminal drug policy in the Netherlands.

  17. Drug: D06717 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 0 Crude drugs D06717 Safflower (JP16) Traditional Chinese Medicine in Japan [BR:br08304] Crude Drugs Drugs for blood Drugs... for removing blood stasis D06717 *Safflower; Safflower Drugs for external use Drugs

  18. Drug: D06912 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available nese Medicine in Japan [BR:br08304] Crude Drugs Drugs for blood Drugs for removing blood stasis D06912 *Quercus cortex; Bokusoku Drug...s for external use Drugs for external use D06912 *Quercu

  19. Attitudes towards drug legalization among drug users.

    Science.gov (United States)

    Trevino, Roberto A; Richard, Alan J

    2002-01-01

    Research shows that support for legalization of drugs varies significantly among different sociodemographic and political groups. Yet there is little research examining the degree of support for legalization of drugs among drug users. This paper examines how frequency and type of drug use affect the support for legalization of drugs after adjusting for the effects of political affiliation and sociodemographic characteristics. A sample of 188 drug users and non-drug users were asked whether they would support the legalization of marijuana, cocaine, and heroin. Respondents reported their use of marijuana, crack, cocaine, heroin, speedball, and/or methamphetamines during the previous 30 days. Support for legalization of drugs was analyzed by estimating three separate logistic regressions. The results showed that the support for the legalization of drugs depended on the definition of "drug user" and the type of drug. In general, however, the results showed that marijuana users were more likely to support legalizing marijuana, but they were less likely to support the legalization of cocaine and heroin. On the other hand, users of crack, cocaine, heroin, speedball, and/or methamphetamines were more likely to support legalizing all drugs including cocaine and heroin.

  20. Drug Interaction API

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Interaction API is a web service for accessing drug-drug interactions. No license is needed to use the Interaction API. Currently, the API uses DrugBank for its...

  1. Drugs Approved for Leukemia

    Science.gov (United States)

    ... Ask about Your Treatment Research Drugs Approved for Leukemia This page lists cancer drugs approved by the ... not listed here. Drugs Approved for Acute Lymphoblastic Leukemia (ALL) Abitrexate (Methotrexate) Arranon (Nelarabine) Asparaginase Erwinia chrysanthemi ...

  2. Prescription Drug Abuse

    Science.gov (United States)

    ... a drug abuser aggressive or paranoid. Although stimulant abuse might not lead to physical dependence and withdrawal, the feelings these drugs give people can cause them to use the drugs more and more ...

  3. Drug Retention Times

    Energy Technology Data Exchange (ETDEWEB)

    Center for Human Reliability Studies

    2007-05-01

    The purpose of this monograph is to provide information on drug retention times in the human body. The information provided is based on plausible illegal drug use activities that might be engaged in by a recreational drug user

  4. Drug Retention Times

    Energy Technology Data Exchange (ETDEWEB)

    Center for Human Reliability Studies

    2007-05-01

    The purpose of this monograph is to provide information on drug retention times in the human body. The information provided is based on plausible illegal drug use activities that might be engaged in by a recreational drug user.

  5. Drug-induced hepatitis

    Science.gov (United States)

    Toxic hepatitis ... to get liver damage. Some drugs can cause hepatitis with small doses, even if the liver breakdown ... liver. Many different drugs can cause drug-induced hepatitis. Painkillers and fever reducers that contain acetaminophen are ...

  6. Drug Development Process

    Science.gov (United States)

    ... Device Approvals The Drug Development Process The Drug Development Process Share Tweet Linkedin Pin it More sharing ... Pin it Email Print Step 1 Discovery and Development Discovery and Development Research for a new drug ...

  7. [Epigenetics and drug addiction: a focus on MeCP2 and on histone acetylation].

    Science.gov (United States)

    Zwiller, Jean

    2015-04-01

    Chronic drug exposure alters gene expression in the brain, which is believed to underlie compulsive drug seeking and drug taking behavior. Recent evidence shows that drug-induced long-term neuroadaptations in the brain are mediated in part by epigenetic mechanisms. By remodeling chromatin, this type of regulation contributes to drug-induced synaptic plasticity that translates into behavioral modifications. How drug-induced alterations in DNA methylation regulate gene expression is reviewed here, with a focus on MeCP2, a protein binding methylated DNA. The importance of histone modifications, especially acetylation is also discussed, with an emphasis on the effects of inhibitors of histone deacetylases on drug-induced behavioral changes. The precise identification of the epigenetic mechanisms that are under the control of drugs of abuse may help to uncover novel targets for the treatment of drug seeking and relapse. PMID:25958763

  8. Art as Alterity in Education

    Science.gov (United States)

    Zhao, Guoping

    2014-01-01

    In education, art has often been perceived as entertainment and decoration and is the first subject to go when there are budget cuts or test-score pressures. Drawing on Emmanuel Lévinas's idea of the primacy of radical alterity that breaks the totality of our being, enables self-transformation and ethics, and ensures community as a totality…

  9. Nuclear Receptors in Drug Metabolism, Drug Response and Drug Interactions

    Directory of Open Access Journals (Sweden)

    Chandra Prakash

    2015-12-01

    Full Text Available Orally delivered small-molecule therapeutics are metabolized in the liver and intestine by phase I and phase II drug-metabolizing enzymes (DMEs, and transport proteins coordinate drug influx (phase 0 and drug/drug-metabolite efflux (phase III. Genes involved in drug metabolism and disposition are induced by xenobiotic-activated nuclear receptors (NRs, i.e. PXR (pregnane X receptor and CAR (constitutive androstane receptor, and by the 1α, 25-dihydroxy vitamin D3-activated vitamin D receptor (VDR, due to transactivation of xenobiotic-response elements (XREs present in phase 0-III genes. Additional NRs, like HNF4-α, FXR, LXR-α play important roles in drug metabolism in certain settings, such as in relation to cholesterol and bile acid metabolism. The phase I enzymes CYP3A4/A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, CYP1A2, CYP2C8, CYP2A6, CYP2J2, and CYP2E1 metabolize >90% of all prescription drugs, and phase II conjugation of hydrophilic functional groups (with/without phase I modification facilitates drug clearance. The conjugation step is mediated by broad-specificity transferases like UGTs, SULTs, GSTs. This review delves into our current understanding of PXR/CAR/VDR-mediated regulation of DME and transporter expression, as well as effects of single nucleotide polymorphism (SNP and epigenome (specified by promoter methylation, histone modification, microRNAs, long non coding RNAs on the expression of PXR/CAR/VDR and phase 0-III mediators, and their impacts on variable drug response. Therapeutic agents that target epigenetic regulation and the molecular basis and consequences (overdosing, underdosing, or beneficial outcome of drug-drug/drug-food/drug-herb interactions are also discussed. Precision medicine requires understanding of a drug's impact on DME and transporter activity and their NR-regulated expression in order to achieve optimal drug efficacy without adverse drug reactions. In future drug screening, new tools such as humanized mouse

  10. Enteral drug absorption in patients with short small bowel : a review.

    NARCIS (Netherlands)

    Severijnen, R.S.V.M.; Bayat, N.; Bakker, H.; Tolboom, J.J.M.; Bongaerts, G.P.A.

    2004-01-01

    Drug therapy may become difficult when a significant amount of the small intestine is resected, as happens in patients with a short small bowel. Drug absorption from the gastrointestinal tract is altered in these patients; however, this effect is variable in patients and differs with each drug. Lite

  11. Neuroimmune mechanisms of alcohol and drug addiction.

    Science.gov (United States)

    Cui, Changhai; Shurtleff, David; Harris, R Adron

    2014-01-01

    Alcohol and other drugs of abuse have significant impacts on the neuroimmune system. Studies have demonstrated that drugs of abuse interact with the neuroimmune system and alter neuroimmune gene expression and signaling, which in turn contribute to various aspects of addiction. As the key component of the CNS immune system, neuroimmune factors mediate neuroinflammation and modulate a wide range of brain function including neuronal activity, endocrine function, and CNS development. These neuromodulatory properties of immune factors, together with their essential role in neuroinflammation, provide a new framework to understand neuroimmune mechanisms mediating brain functional and behavioral changes contributing to addiction. This chapter highlights recent advances in understanding neuroimmune changes associated with exposure to alcohol and other drugs of abuse, including opiates, marijuana, methamphetamine, and cocaine. It provides a brief overview on what we know about neuroimmune signaling and its role in drug action and addiction. PMID:25175859

  12. Psychotropic drugs and the aging patient.

    Science.gov (United States)

    Pollock, B G

    1998-09-01

    Patients older than age 65 currently compose 13% of the US population, yet they receive 35% of all prescribed medications. In older patients, the complications of psychotropic drugs alone constitute a highly significant health problem. Pharmacokinetic and pharmacodynamic differences secondary to age or illness require careful consideration. Accumulation of drug might result from declining cardiovascular or renal function, alteration of body composition, or genetic or acquired inhibition of drug metabolism. As patients age, there is a general reduction in homeostatic mechanisms such as postural control, orthostatic circulatory responses, and visceral muscle function that may result in adverse drug experiences. specific receptor and neurotransmitter changes associated with senescence include reductions in central cholinergic and dopaminergic activities that lead to greater sensitivity to medications acting on these systems. Clinical vigilance is particularly important when prescribing newly available antidepressants and antipsychotics, since typically these medications are not systematically evaluated in older subjects before their release. PMID:9745631

  13. Drug: D06770 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available ommia family) Eucommia bark (dried) Major component: Gutta-percha Therapeutic category of drugs in Japan [BR:br08301] 5 Crude drugs... and Chinese medicine formulations 51 Crude drugs 510 Crude drugs 5100 Crude drugs D0...e Drugs Drugs for Qi Drugs for replenishing Qi D06770 Eucommia bark Crude drugs [BR:br08305] Dicot plants: a

  14. Genetic and epigenetic alterations of the reduced folate carrier in untreated diffuse large B-cell lymphoma

    DEFF Research Database (Denmark)

    Kastrup, Ingelise Bjerring; Worm, Jesper; Ralfkiaer, Elisabeth;

    2007-01-01

    The reduced folate carrier (RFC) is a transmembrane protein that mediates cellular uptake of reduced folates and antifolate drugs, including methotrexate (MTX). Acquired alterations of the RFC gene have been associated with resistance to MTX in cancer cell lines and primary osteosarcomas. Here, w...... with adverse outcome. In DLBCL, genetic and epigenetic alterations of RFC were detected at diagnosis in the absence of a selective MTX pressure, suggesting that these alterations may possibly contribute to the development of lymphoma. Udgivelsesdato: 2008-Jan...

  15. Genetic and epigenetic alterations of the reduced folate carrier in untreated diffuse large B-cell lymphoma

    DEFF Research Database (Denmark)

    Kastrup, I.B.; Worm, J.; Ralfkiaer, E.;

    2008-01-01

    The reduced folate carrier (RFC) is a transmembrane protein that mediates cellular uptake of reduced folates and antifolate drugs, including methotrexate (MTX). Acquired alterations of the RFC gene have been associated with resistance to MTX in cancer cell lines and primary osteosarcomas. Here, w...... with adverse outcome. In DLBCL, genetic and epigenetic alterations of RFC were detected at diagnosis in the absence of a selective MTX pressure, suggesting that these alterations may possibly contribute to the development of lymphoma Udgivelsesdato: 2008/1...

  16. Usefulness of tirapazamine as a combined agent in chemoradiation and thermo-chemoradiation therapy at mild temperatures. Reference to the effect on intratumor quiescent cells

    International Nuclear Information System (INIS)

    C3H/He mice bearing SCC VII tumors received 5-bromo-2'-deoxyuridine (BrdU) continuously for 5 days via implanted mini-osmotic pumps to label all proliferating (P) cells. The mice then received one of six different DNA-damaging agents with or without mild temperature hyperthermia (40 deg C, 30 min, MTH). These agents were adriamycin (ADM), mitomycin C (MMC), cyclophosphamide (CPA), bleomycin (BLM), cisplatin (CDDP), and tirapazamine (TPZ). After the drug treatment, the tumor-bearing mice were irradiated with a series of doses of γ-rays. Immediately after irradiation, the tumors were excised, minced and trypsinized. The tumor cell suspensions thus obtained were incubated with cytochalasin-B (a cytokinesis blocker), and the micronucleus (MN) frequency in cells without BrdU labeling (=quiescent (Q) cells) was determined using immunofluorescence staining for BrdU. The MN frequency in the total (P+Q) tumor cells was determined from the tumors that had not been pretreated with BrdU. MTH significantly increased the MN frequency of total cells in tumors irradiated with γ-rays combined with CPA, BLM, CDDP or TPZ, and that of Q cells in tumors irradiated with γ-rays combined with BLM or TPZ. The sensitivity difference in the MN frequency between total and Q tumor cells was significantly decreased by the combination with TPZ. TPZ combined with radiotherapy and TPZ combined with thermo-radiotherapy at mild temperatures appear to be promising modalities for sensitizing tumor cells in vivo, including Q tumor cells. (author)

  17. Use of antiarrhythmic drugs in elderly patients

    Institute of Scientific and Technical Information of China (English)

    Hon-Chi Lee; Kristin TL Huang; Win-Kuang Shen

    2011-01-01

    Human aging is a global issue with important implications for current and future incidence and prevalence of health conditions and disability.Cardiac arrhythmias,including atrial fibrillation,sudden cardiac death,and bradycardia requiring pacemaker placement,all increase exponentially after the age of 60.It is important to distinguish between the normal,physiological consequences of aging on cardiacelectrophysiology and the abnormal,pathological alterations.The age-related cardiac changes include ventricular hypertrophy,senileamyloidosis,cardiac valvular degenerative changes and annular calcification,fibrous infiltration of the conduction system,and loss of naturalpacemaker cells and these changes could have a profound effect on the development of arrhythmias.The age-related cardiac electrophysiological changes include up- and down-regulation of specific ion channel expression and intracellular Ca2+ overload which promote the development of cardiac an-hythmias.As ion channels are the substrates of antiarrhythmic drugs,it follows that the pharmacoldnetics and pharmacodynamics of these drugs will also change with age.Aging alters the absorption,distribution,metabolism,and elimination of antiarrhythmic drugs,so liver and kidney function must be monitored to avoid potential adverse drug effects,and antiarrhythmic dosing may need to be adjusted for age.Elderly patients are also more susceptible to the side effects of many antiarrhythmics,including bradycardia,orthostatic hypotension,urinary retention,and falls.Moreover,the choice of antiarrhythmic drugs in the elderly patient is frequently complicated by the presence of co-morbid conditions and by polyphanmacy,and the astute physician must pay careful attention to potential drug-drug interactions.Finally,it is important to remember that the use of antiarrhythmic drugs in elderly patients must be individualized and tailored to each patient's physiology,disease processes,and medication regimen.

  18. Young drug addicts and the drug scene.

    Science.gov (United States)

    Lucchini, R

    1985-01-01

    The drug scene generally comprises the following four distinct categories of young people: neophytes, addicts who enjoy a high status vis-à-vis other addicts, multiple drug addicts, and non-addicted drug dealers. It has its own evolution, hierarchy, structure and criteria of success and failure. The members are required to conform to the established criteria. The integration of the young addict into the drug scene is not voluntary in the real sense of the word, for he is caught between the culture that he rejects and the pseudo-culture of the drug scene. To be accepted into the drug scene, the neophyte must furnish proof of his reliability, which often includes certain forms of criminal activities. The addict who has achieved a position of importance in the drug world serves as a role model for behaviour to the neophyte. In a more advanced phase of addiction, the personality of the addict and the social functions of the drug scene are overwhelmed by the psychoactive effects of the drug, and this process results in the social withdrawal of the addict. The life-style of addicts and the subculture they develop are largely influenced by the type of drug consumed. For example, it is possible to speak of a heroin subculture and a cocaine subculture. In time, every drug scene deteriorates so that it becomes fragmented into small groups, which is often caused by legal interventions or a massive influx of new addicts. The fragmentation of the drug scene is followed by an increase in multiple drug abuse, which often aggravates the medical and social problems of drug addicts. PMID:4075000

  19. CONCEPT OF DRUG INTERACTION

    Directory of Open Access Journals (Sweden)

    Singh Nidhi

    2012-07-01

    Full Text Available Drug interaction is an increasingly important cause of adverse reactions (ADR, and is the modification of the effect of one drug (object by the prior or concomitant administration of another drug (precipitant drug. Drug interaction may either enhance or diminish the intended effect of one or both drugs. For example severe haemorrhage may occur if warfarin and salicylates (asprin are combined. Precipitant drugs modify the object drug's absorption, distribution, metabolism, excretion or actual clinical effect. Nonsteroidal anti-inflammatory drugs, antibiotics and, in particular, rifampin are common precipitant drugs prescribed in primary care practice. Drugs with a narrow therapeutic range or low therapeutic index are more likely to be the objects for serious drug interactions. Object drugs in common use include warfarin, fluoroquinolones, antiepileptic drugs, oral contraceptives, cisapride and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Many other drugs, act as precipitants or objects, and a number of drugs act as both. The aim of present review is to throw light on the concept of drug interaction.

  20. Neurobehavioral Alterations in HIV-1 Transgenic Rats: Evidence for Dopaminergic Dysfunction

    OpenAIRE

    Moran, L. M.; Booze, R.M.; Webb, K. M.; Mactutus, C. F.

    2012-01-01

    Clinical studies have provided evidence that the progression of HIV-1-associated neurocognitive disorders (HAND) involves alterations in dopamine (DA) systems. Drugs of abuse that act on the brain DA system, such as cocaine (Coc), may exacerbate HIV-1 infection and consequent behavioral and neurological manifestations. In the present study, we used the HIV-1 transgenic (Tg) rat, which constitutively expresses 7 of the 9 HIV-1 genes, to assess potential DA system alterations in three behaviora...

  1. General Anesthesia and Altered States of Arousal: A Systems Neuroscience Analysis

    OpenAIRE

    Emery N Brown; Purdon, Patrick L.; Van Dort, Christa J.

    2011-01-01

    Placing a patient in a state of general anesthesia is crucial for safely and humanely performing most surgical and many nonsurgical procedures. How anesthetic drugs create the state of general anesthesia is considered a major mystery of modern medicine. Unconsciousness, induced by altered arousal and/or cognition, is perhaps the most fascinating behavioral state of general anesthesia. We perform a systems neuroscience analysis of the altered arousal states induced by five classes of intraveno...

  2. Characterizing genomic alterations in cancer by complementary functional associations | Office of Cancer Genomics

    Science.gov (United States)

    Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment.

  3. 125I-UdR瘤内注射治疗Lewis肺癌荷瘤小鼠效果观察%Therapeutic effect of intratumoral injection using 125I-UdR on Lewis lung cancer

    Institute of Scientific and Technical Information of China (English)

    李智勇; 刘增礼; 吴锦昌; 周俊东; 申咏梅; 劳勤华

    2013-01-01

    目的 研究125I标记脱氧尿嘧啶核苷(125I-UdR)在Lewis肺癌荷瘤小鼠模型治疗中的药物分布、用药安全性和治疗效果.方法 在Lewis肺癌荷瘤小鼠模型瘤内注射125I-UdR(3.7 MBq/10 μL),通过γ-计数器测量各脏器放射性活度和SPECT显像来观察125I-UdR的药物分布;分析用药后外周血象、肝肾功能等指标及骨髓象来评价125I-UdR的安全性;观察用药后瘤体的组织细胞学变化并作生存分析.结果 125I-UdR局部注射后可在瘤内持续浓聚并致肿瘤细胞坏死;其外周血象、肝肾功能和骨髓象无明显变化,接受治疗的荷瘤鼠生存期明显延长.结论 荷瘤鼠瘤内注射125I-UdR治疗Lewis肺癌安全有效.%Objective To investigate the distribution,safety and therapeutic effect of 125I-UdR (5-[125I] Iodo-2-deoxyuridine) (3.7 MBq/10 ul) in C57 BL/6 mice bearing Lewis lung cancer.Methods After 125I-UdR intratumoral injection,the radioactivity of various organs was determined by γ-well counter and the distribution of 125 I-UdR was observed by SPECT scintigraphy; the safety of 125 I-UdR was analyzed by observing peripheral hemogram,marrow cell and blood biochemistry indexes; the changes of histology and cytology of the tumor were observed and the survival rate was analyzed.Results 125I-UdR was persistently stayed in the tumor,and led to tumor necrosis after partly intratumoral injection.Mice hemogram,marrow cell,hepatic and renal function had no obvious changes,and the survival time of tumor-bearing mice treated by 125 I-UdR distinctly was extended.Conclusion It is safe and effective to inject 125I-UdR (3.7 MBq/10 ul) into the transplanting tumor of tumor-bearing mice with Lewis lung cancer.

  4. Pharmacokinetic strategies to improve drug penetration and entrapment within solid tumors.

    Science.gov (United States)

    Al-Abd, Ahmed M; Aljehani, Zekra K; Gazzaz, Rana W; Fakhri, Sarah H; Jabbad, Aisha H; Alahdal, Abdulrahman M; Torchilin, Vladimir P

    2015-12-10

    Despite the discovery of a large number of anticancer agents, cancer still remains among the leading causes of death since the middle of the twentieth century. Solid tumors possess a high degree of genetic instability and emergence of treatment resistance. Tumor resistance has emerged for almost all approved anticancer drugs and will most probably emerge for newly discovered anticancer agents as well. The use of pharmacokinetic approaches to increase anticancer drug concentrations within the solid tumor compartment and prolong its entrapment might diminish the possibility of resistance emergence at the molecular pharmacodynamic level and might even reverse tumor resistance. Several novel treatment modalities such as metronomic therapy, angiogenesis inhibitors, vascular disrupting agents and tumor priming have been introduced to improve solid tumor treatment outcomes. In the current review we will discuss the pharmacokinetic aspect of these treatment modalities in addition to other older treatment modalities, such as extracellular matrix dissolving agents, extracellular matrix synthesis inhibitors, chemoembolization and cellular efflux pump inhibition. Many of these strategies showed variable degrees of success/failure; however, reallocating these modalities based on their influence on the intratumoral pharmacokinetics might improve their understanding and treatment outcomes. PMID:26342660

  5. [Factors that alter taste perception].

    Science.gov (United States)

    Maffeis, E R; Silva-Netto, C R

    1990-01-01

    Dysfunction of taste perception is a significant problem for many individuals. Taste anomalies may affect health not only by directly affecting liquid and solid food intake, but also by creating a state of depression due to the loss of an important source of pleasure. Many factors alter taste perception, such as lesions of the oral mucosa, cigarette smoking, radiation, chemotherapy, renal disease, hepatitis, leprosy, hormones, nutrition, use of dentures, medications, and aging. Gum or ice chewing may temporarily help loss of taste. Patients should be encouraged to chew their food thoroughly, alternating the sides of the mouth, or alternating different foods. Unfortunately, in many cases there is no cure for this alteration, and patience is then the only possibility.

  6. Flap Conformations in HIV-1 Protease are Altered by Mutations

    Science.gov (United States)

    Fanucci, Gail; Blackburn, Mandy; Veloro, Angelo; Galiano, Luis; Fangu, Ding; Simmerling, Carlos

    2009-03-01

    HIV-1 protease (PR) is an enzyme that is a major drug target in the treatment of AIDS. Although the structure and function of HIV-1 PR have been studied for over 20 years, questions remain regarding the conformations and dynamics of the β-hairpin turns (flaps) that cover the active site cavity. Distance measurements with pulsed EPR spectroscopy of spin labeled constructs of HIV-1 PR have been used to characterize the flap conformations in the apo and inhibitor bound states. From the most probably distances and the breadth of the distance distribution profiles from analysis of the EPR data, insights regarding the flap conformations and flexibility are gained. The EPR results clearly show how drug pressure selected mutations alter the average conformation of the flaps and the degree of opening of the flaps. Molecular dynamics simulations successfully regenerate the experimentally determined distance distribution profiles, and more importantly, provide structural models for full interpretation of the EPR results. By combining experiment and theory to understand the role that altered flap flexibility/conformations play in the mechanism of drug resistance, key insights are gained toward the rational development of new inhibitors of this important enzyme.

  7. Buccal alterations in diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Negrato Carlos

    2010-01-01

    Full Text Available Abstract Long standing hyperglycaemia besides damaging the kidneys, eyes, nerves, blood vessels, heart, can also impair the function of the salivary glands leading to a reduction in the salivary flow. When salivary flow decreases, as a consequence of an acute hyperglycaemia, many buccal or oral alterations can occur such as: a increased concentration of mucin and glucose; b impaired production and/or action of many antimicrobial factors; c absence of a metalloprotein called gustin, that contains zinc and is responsible for the constant maturation of taste papillae; d bad taste; e oral candidiasis f increased cells exfoliation after contact, because of poor lubrication; g increased proliferation of pathogenic microorganisms; h coated tongue; i halitosis; and many others may occur as a consequence of chronic hyperglycaemia: a tongue alterations, generally a burning mouth; b periodontal disease; c white spots due to demineralization in the teeth; d caries; e delayed healing of wounds; f greater tendency to infections; g lichen planus; h mucosa ulcerations. Buccal alterations found in diabetic patients, although not specific of this disease, have its incidence and progression increased when an inadequate glycaemic control is present.

  8. Drug therapy during pregnancy: implications for dental practice.

    Science.gov (United States)

    Ouanounou, A; Haas, D A

    2016-04-22

    Pregnancy is accompanied by various physiological and physical changes, including those found in the cardiovascular, respiratory, gastrointestinal, renal and haematological systems. These alterations in the pregnant patient may potentially affect drug pharmacokinetics. Also, pharmacotherapy presents a unique matter due to the potential teratogenic effects of certain drugs. Although medications prescribed by dentists are generally safe during pregnancy, some modifications may be needed. In this article we will discuss the changes in the physiology during pregnancy and its impact on drug therapy. Specific emphasis will be given to the drugs commonly given by dentists, namely, local anaesthetics, analgesics, antibiotics and sedatives.

  9. Drug therapy during pregnancy: implications for dental practice.

    Science.gov (United States)

    Ouanounou, A; Haas, D A

    2016-04-22

    Pregnancy is accompanied by various physiological and physical changes, including those found in the cardiovascular, respiratory, gastrointestinal, renal and haematological systems. These alterations in the pregnant patient may potentially affect drug pharmacokinetics. Also, pharmacotherapy presents a unique matter due to the potential teratogenic effects of certain drugs. Although medications prescribed by dentists are generally safe during pregnancy, some modifications may be needed. In this article we will discuss the changes in the physiology during pregnancy and its impact on drug therapy. Specific emphasis will be given to the drugs commonly given by dentists, namely, local anaesthetics, analgesics, antibiotics and sedatives. PMID:27103292

  10. Drug hypersensitivity syndrome

    OpenAIRE

    Rashmi Kumari; Dependra K Timshina; Devinder Mohan Thappa

    2011-01-01

    Drug hypersensitivity syndrome (DHS) is an adverse drug reaction commonly associated with the aromatic antiepileptic drugs (AEDs), viz., phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), lamotrigine, primidone, etc. It can also be caused by other drugs, such as sulfonamides, dapsone, minocycline, gold derivatives, cyclosporine, captopril, diltiazem, terbinafine, azathioprine and allopurinol. Diagnosis of DHS may be difficult because of the variety of clinical and laboratory abnormalit...

  11. Drugs and Young People

    Science.gov (United States)

    Drug abuse is a serious public health problem. It affects almost every community and family in some way. Drug abuse in children and teenagers may pose a ... of young people may be more susceptible to drug abuse and addiction than adult brains. Abused drugs ...

  12. Nicotinic alteration of decision-making.

    Science.gov (United States)

    Naudé, Jérémie; Dongelmans, Malou; Faure, Philippe

    2015-09-01

    Addiction to nicotine is characterized by impulses, urges and lack of self-control towards cigarettes. A key element in the process of addiction is the development of habits oriented towards nicotine consumption that surpass flexible systems as a consequence of a gradual adaptation to chronic drug exposure. However, the long-term effects of nicotine on brain circuits also induce wide changes in decision-making processes, affecting behaviors unrelated to cigarettes. This review aims at providing an update on the implications of nicotine on general decision-making processes, with an emphasis on impulsivity and risk-taking. As impulsivity is a rather ambiguous behavioral trait, we build on economic and normative theories to better characterize these nicotine-induced alterations in decision-making. Nonetheless, experimental data are sparse and often contradictory. We will discuss how the latest findings on the neurobiological basis of choice behavior may help disentangling these issues. We focus on the role of nicotine acetylcholine receptors and their different subunits, and on the spatio-temporal dynamics (i.e. diversity of the neural circuits, short- and long-term effects) of both endogenous acetylcholine and nicotine action. Finally, we try to link these neurobiological results with neuro-computational models of attention, valuation and action, and of the role of acetylcholine in these decision processes. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. PMID:25498234

  13. Neuroimaging in nuclear medicine: drug addicted brain

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Yong-An; Kim, Dae-Jin [The Catholic University of Korea, Seoul (Korea, Republic of)

    2006-02-15

    Addiction to illicit drugs in one of today's most important social issues. Most addictive drugs lead to irreversible parenchymal changes in the human brain. Neuroimaging data bring to light the pharmacodynamics and pharmacokinetics of the abused drugs, and demonstrate that addiction is a disease of the brain. Continuous researches better illustrate the neurochemical alterations in brain function, and attempt to discover the links to consequent behavioral changes. Newer hypotheses and theories follow the numerous results, and more rational methods of approaching therapy are being developed. Substance abuse is on the rise in Korea, and social interest in the matter as well. On the other hand, diagnosis and treatment of drug addiction is still very difficult, because how the abused substance acts in the brain, or how it leads to behavioral problems in not widely known. Therefore, understanding the mechanism of drug addiction can improve the process of diagnosing addict patients, planning therapy, and predicting the prognosis . Neuroimaging approaches by nuclear medicine methods are expected to objectively judge behavioral and neurochemical changes, and response to treatment. In addition, as genes associated with addictive behavior are discovered, functional nuclear medicine images will aid in the assessment of individuals. Reviewing published literature on neuroimaging regarding nuclear medicine is expected to be of assistance to the management of drug addict patients. What's more, means of applying nuclear medicine to the care of drug addict patients should be investigated further.

  14. Neuroimaging in nuclear medicine: drug addicted brain

    International Nuclear Information System (INIS)

    Addiction to illicit drugs in one of today's most important social issues. Most addictive drugs lead to irreversible parenchymal changes in the human brain. Neuroimaging data bring to light the pharmacodynamics and pharmacokinetics of the abused drugs, and demonstrate that addiction is a disease of the brain. Continuous researches better illustrate the neurochemical alterations in brain function, and attempt to discover the links to consequent behavioral changes. Newer hypotheses and theories follow the numerous results, and more rational methods of approaching therapy are being developed. Substance abuse is on the rise in Korea, and social interest in the matter as well. On the other hand, diagnosis and treatment of drug addiction is still very difficult, because how the abused substance acts in the brain, or how it leads to behavioral problems in not widely known. Therefore, understanding the mechanism of drug addiction can improve the process of diagnosing addict patients, planning therapy, and predicting the prognosis . Neuroimaging approaches by nuclear medicine methods are expected to objectively judge behavioral and neurochemical changes, and response to treatment. In addition, as genes associated with addictive behavior are discovered, functional nuclear medicine images will aid in the assessment of individuals. Reviewing published literature on neuroimaging regarding nuclear medicine is expected to be of assistance to the management of drug addict patients. What's more, means of applying nuclear medicine to the care of drug addict patients should be investigated further

  15. Macrolide antibacterials. Drug interactions of clinical significance.

    Science.gov (United States)

    von Rosensteil, N A; Adam, D

    1995-08-01

    Macrolide antibiotics can interact adversely with commonly used drugs, usually by altering metabolism due to complex formation and inhibition of cytochrome P-450 IIIA4 (CYP3A4) in the liver and enterocytes. In addition, pharmacokinetic drug interactions with macrolides can result from their antibiotic effect on microorganisms of the enteric flora, and through enhanced gastric emptying due to a motilin-like effect. Macrolides may be classified into 3 different groups according to their affinity for CYP3A4, and thus their propensity to cause pharmacokinetic drug interactions. Troleandomycin, erythromycin and its prodrugs decrease drug metabolism and may produce drug interactions (group 1). Others, including clarithromycin, flurithromycin, midecamycin, midecamycin acetate (miocamycin; ponsinomycin), josamycin and roxithromycin (group 2) rarely cause interactions. Azithromycin, dirithromycin, rikamycin and spiramycin (group 3) do not inactivate CYP3A4 and do not engender these adverse effects. Drug interactions with carbamazepine, cyclosporin, terfenadine, astemizole and theophylline represent the most frequently encountered interactions with macrolide antibiotics. If the combination of a macrolide and one of these compounds cannot be avoided, serum concentrations of concurrently administered drugs should be monitored and patients observed for signs of toxicity. Rare interactions and those of dubious clinical importance are those with alfentanil and sufentanil, antacids and cimetidine, oral anticoagulants, bromocriptine, clozapine, oral contraceptive steroids, digoxin, disopyramide, ergot alkaloids, felodipine, glibenclamide (glyburide), levodopa/carbidopa, lovastatin, methylprednisolone, phenazone (antipyrine), phenytoin, rifabutin and rifampicin (rifampin), triazolam and midazolam, valproic acid (sodium valproate) and zidovudine. PMID:7576262

  16. Altered membrane lipid dynamics and chemoprevention by non-steroidal anti inflammatory drugs during colon carcinogenesis Alteración de la dinámica de los lípidos de membrana y quimioprevención mediante los fármacos antiinflamatorios no esteroideos en la carcinogénesis de colon

    OpenAIRE

    S. Singh Kanwar; V. Vaish; S. Nath Sanya

    2011-01-01

    The present work focuses on the anti-neoplastic role of non steroidal anti-inflammatory drugs (NSAIDs) in modulating the biophysical parameters of the colonic membranes in 1,2-dimethylhydrazine dihydrochloride (DMH) induced carcinogenesis. The steady-state fluorescence polarization technique was applied to assess membrane fluidity, membrane polarity and lipid phase states. The decline in cholesterol content, biosynthesis and cholesterol: phospholipids ratio with DMH treatment indicates more f...

  17. Food and drugs

    Directory of Open Access Journals (Sweden)

    Đaković-Švajcer Kornelija

    2002-01-01

    Full Text Available Food can exert a significant influence on the effects of certain drugs. The interactions between food and drugs can be pharmacokinetic and pharmacodynamic. Pharmacokinetic interactions most often take place on absorption and drug metabolism levels. Absorption can be either accelerated or delayed, increased or decreased, while drug metabolism can be either stimulated or inhibited. The factors which influence food-drug interactions are as follows: composition and physic-chemical properties of drugs, the interval between a meal and drug intake and food composition. Food consistency is of lesser influence on drug bioavailability than food composition (proteins, fats, carbohydrates, cereals. Important interactions can occur during application of drugs with low therapeutic index, whereby the plasma level significantly varies due to changes in resorption or metabolism (e.g. digoxin, theophyllin, cyclosporin and drugs such as antibiotics, whose proper therapeutic effect requires precise plasma concentrations.

  18. Resistance to chemotherapy is associated with altered glucose metabolism in acute myeloid leukemia

    OpenAIRE

    SONG, KUI; Li, Min; Xu, Xiaojun; Xuan, Li; HUANG, GUINIAN; Liu, Qifa

    2016-01-01

    Altered glucose metabolism has been described as a cause of chemoresistance in multiple tumor types. The present study aimed to identify the expression profile of glucose metabolism in drug-resistant acute myeloid leukemia (AML) cells and provide potential strategies for the treatment of drug-resistant AML. Bone marrow and serum samples were obtained from patients with AML that were newly diagnosed or had relapsed. The messenger RNA expression of hypoxia inducible factor (HIF)-1α, glucose tra...

  19. Practice Gaps: Drug Reactions.

    Science.gov (United States)

    Wolverton, Stephen E

    2016-07-01

    The term "drug reactions" is relevant to dermatology in three categories of reactions: cutaneous drug reactions without systemic features, cutaneous drug reactions with systemic features, and systemic drugs prescribed by the dermatologist with systematic adverse effects. This article uses examples from each of these categories to illustrate several important principles central to drug reaction diagnosis and management. The information presented will help clinicians attain the highest possible level of certainty before making clinical decisions. PMID:27363888

  20. Antiepileptic drugs: newer targets and new drugs

    OpenAIRE

    Vihang S. Chawan; Abhishek M. Phatak; Kalpesh V. Gawand; Sagar V. Badwane; Sagar S. Panchal

    2016-01-01

    Epilepsy is a common neurological disorder affecting 0.5-1% of the population in India. Majority of patients respond to currently available antiepileptic drugs (AEDs), but a small percentage of patients have shown poor and inadequate response to AEDs in addition to various side effects and drug interactions while on therapy. Thus there is a need to develop more effective AEDs in drug resistant epilepsy which have a better safety profile with minimal adverse effects. The United States food and...

  1. Hepatic histological alterations and biochemical changes induced by sildenafil overdoses.

    Science.gov (United States)

    Jarrar, Bashir Mahmoud; Almansour, Mansour Ibrahim

    2015-11-01

    Sildenafil is used for the treatment of erectile dysfunction and is helping millions of men around the world to achieve and maintain a long lasting erection. Fifty healthy male rabbits (Oryctolagus cuniculus) were used in the present study and exposed daily to sildenafil (0, 1, 3, 6, 9 mg/kg) for 5 days per week for 7 weeks to investigate the biochemical changes and alterations in the hepatic tissues induced by this drug overdosing. In comparison with respective control rabbits, sildenafil overdoses elevated significantly (p-value<0.05, ANOVA test) alanine aminotransferase (ALT), aspartate aminotransferase (AST), testosterone, follicular stimulating hormone and total protein, while creatinine and urea were lowered with no significant alteration was observed in uric acid and luteinizing hormone concentration. Also sildenafil provoked hepatocytes nuclear alterations, necrosis, hydropic degeneration, bile duct hyperplasia, Kupffer cells hyperplasia, inflammatory cells infiltration, hepatic vessels congestion and evident partial depletion of glycogen content. The results show that subchronic exposure to sildenafil overdoses exhibits significant biochemical and alterations in the hepatic tissues that might affect the functions of the liver and other vital organs. PMID:26639481

  2. Stress modification of the toxicity of antimotion sickness drugs and Aspirin

    Science.gov (United States)

    Shields, D.; Marra, C.; Goodwin, A.; Vernikos-Danellis, J.

    1975-01-01

    The effect of environmental temperature on the toxicity of cyclizine, trimethobenzamide, and Aspirin were studied in mice. LD-50s were compared at 30 C, 22 C, and 15 C. At 30 C the toxicity of all three drugs increased, with that to Aspirin being affected most. Cooling decreased the toxicity of cyclizine and had no significant effect on that of trimethobenzamide or aspirin. These findings indicate that alterations in environmental temperature markedly affect drug toxicity. They emphasize that such alterations, and particularly increases in temperature, do not have to be particularly drastic, but that 'mild' variations in the environment are effective in altering an animal's sensitivity to a drug.

  3. Drug: D06742 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available Crude drugs D06742 Houttuynia herb (JP16) Traditional Chinese Medicine in Japan [BR:br08304] Crude Drugs Drugs for clearing heat Drug...s for clearing heat D06742 *Houttuynia herb; Houttuynia harb Drugs... for pus discharge Drugs for pus discharge D06742 *Houttuynia herb; Houttuynia harb Crude drugs [B

  4. Metabolic alterations in cancer cells and therapeutic implications

    Institute of Scientific and Technical Information of China (English)

    Naima Hammoudi; Kausar Begam Riaz Ahmed; Celia Garcia-Prieto; Peng Huang

    2011-01-01

    Cancer metabolism has emerged as an important area of research in recent years. Elucidation of the metabolic differences between cancer and normal cells and the underlying mechanisms will not only advance our understanding of fundamental cancer cell biology but also provide an important basis for the development of new therapeutic strategies and novel compounds to selectively eliminate cancer cells by targeting their unique metabolism. This article reviews several important metabolic alterations in cancer cells, with an emphasis on increased aerobic glycolysis (the Warburg effect) and glutamine addiction, and discusses the mechanisms that may contribute to such metabolic changes. In addition, metabolic alterations in cancer stem cells, mitochondrial metabolism and its influence on drug sensitivity, and potential therapeutic strategies and agents that target cancer metabolism are also discussed.

  5. Imaging Receptor Changes in Human Drug Abusers

    OpenAIRE

    Cosgrove, Kelly P

    2010-01-01

    This chapter will review the literature on differences in the brain chemistry of alcohol- and drug-dependent individuals compared to healthy controls as measured with positron emission tomography and single photon emission computed tomography. Specifically, alterations in dopamine, serotonin, opioid, and GABA systems in cocaine, alcohol, nicotine, and heroin dependence have been examined. These neurochemical systems are integrated and play significant roles in a final common pathway mediating...

  6. Neurobiological links between depression and drug dependence

    OpenAIRE

    Gracia Rubio, Irene, 1986-

    2016-01-01

    Early life experiences play a key role in brain function and behaviour. Maternal separation produced negative early life experiences that induce emotional alterations. Contrary, the communal nest has been proposed as a protective model that may reduce the vulnerability of individuals to suffer psychiatric disorders. Moreover, early-life stress enhances the vulnerability to develop substance use disorders, principally during adolescence. Hence, depressive states are associated with drug use di...

  7. Monitoring of drug-drug and drug-food interactions.

    Science.gov (United States)

    Garabedian-Ruffalo, S M; Syrja-Farber, M; Lanius, P M; Plucinski, A

    1988-07-01

    A program for detecting and preventing potentially serious drug-drug and drug-food interactions is described. Two clinical pharmacists developed drug interaction alert (DIA) cards for each potential interaction to be monitored. The cards contain information about the proposed mechanism and potential result of the interaction, as well as information about how to monitor or circumvent the interaction. Staff pharmacists check for the occurrence of potential interactions daily as they verify the filling of the patient-medication cassettes; a poster of all the interactions that are included in the program is posted in each satellite pharmacy to serve as a quick reference for the pharmacists. When a pharmacist detects a potential interaction, he or she completes a DIA card and places it in the medication cassette drawer (if the notice is directed to the nurse) or on the front of the patient's chart (if the notice is directed to the physician). The program was introduced to hospital personnel through inservice education programs and departmental newsletters. The results of a quality assurance review indicated that 95 of 279 (34%) cards dispensed to nurses and 40 of 49 (82%) cards dispensed to physicians resulted in some form of action. The program to detect and prevent potentially serious drug-drug and drug-food interactions has been successful. PMID:3414718

  8. Drug: D06749 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available drugs 5100 Crude drugs D06749 Nuphar rhizome (JP16) Traditional Chinese Medicine in Japan [BR:br08304] Crude Drugs Drugs... for blood Drugs for removing blood stasis D06749 Nuphar rhizome; Nup

  9. Drug: D05431 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available (NF) Traditional Chinese Medicine in Japan [BR:br08304] Crude Drugs Diaphoretic d...rugs Diaphoretic drugs pungent in flavor and cool in property D05431 *Peppermint; Peppermint Drugs for external use Drugs

  10. Drug: D09185 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available Traditional Chinese Medicine in Japan [BR:br08304] Crude Drugs Stomachic and antidiarrheal drugs Stomachic ...and antidiarrheal drugs D09185 *Myrica Drugs for external use Drugs for external use D09185 *Myrica Crude dr

  11. Drug: D03404 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available drugs D03404 Cardamon (JP16); Cardamom seed (NF) Traditional Chinese Medicine in Japan [BR:br08304] Crude Drugs Drugs... for dampness Drugs for resolving dampness D03404 Cardamon; Cardamom seed; Cardamon Crude drugs [B

  12. Drug: D06767 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available gs D06767 Benincasa seed (JP16) Traditional Chinese Medicine in Japan [BR:br08304] Crude Drugs Drugs for blood Drugs... for removing blood stasis D06767 *Benincasa seed Drugs for pus discharge Drugs

  13. Drug: D06772 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available JP16) Traditional Chinese Medicine in Japan [BR:br08304] Crude Drugs Stomachic an...d antidiarrheal drugs Stomachic and antidiarrheal drugs D06772 *Ginseng; Powdered ginseng; Ginseng Drugs for Qi Drugs

  14. Drug: D06803 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 10 Crude drugs 5100 Crude drugs D06803 Nelumbo seed (JP16) Traditional Chinese Medicine in Japan [BR:br08304] Crude Drugs Drugs... for Qi Drugs for replenishing Qi D06803 Nelumbo seed Crude dr

  15. Drug: D06894 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available daisy family) Artemisia leaf (dried) Traditional Chinese Medicine in Japan [BR:br08304] Crude Drugs Drugs for blood Drugs... for replenishing blood D06894 *Artemisiae folium; Gaiyo Drugs for external use Drugs

  16. Drug: D06813 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available nent: Scopoletin [CPD:C01752] Traditional Chinese Medicine in Japan [BR:br08304] Crude Drugs Stomachic and a...ntidiarrheal drugs Stomachic and antidiarrheal drugs D06813 *Dolichos seed Drugs for dampness Drugs

  17. Drug: D09151 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available raditional Chinese Medicine in Japan [BR:br08304] Crude Drugs Drugs for Qi Drugs for regulating Qi D09151 Sw...eetflag rhizome Other drugs Drugs for resuscitation D09151 Acorus gramineus rhizo

  18. Drug: D04705 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 05 Lithospermum root (JP16) Traditional Chinese Medicine in Japan [BR:br08304] Crude Drugs Drugs... for clearing heat Drugs for clearing heat D04705 *Lithospermum root; Lithospermum root Drugs for external use Drugs

  19. Drug: D06736 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available ehmannia root (JP16) Traditional Chinese Medicine in Japan [BR:br08304] Crude Drugs Drugs for replenishing Ying Drugs... for replenishing Ying D06736 *Rehmannia root; Rehmannia root Drugs for blood Drugs for replenishin

  20. Treatment Approaches for Drug Addiction

    Science.gov (United States)

    ... for Drug Addiction DrugFacts: Treatment Approaches for Drug Addiction Email Facebook Twitter Revised July 2016 NOTE: This ... treatment options in your state. What is drug addiction? Drug addiction is a chronic disease characterized by ...

  1. The role of orbitofrontal cortex in drug addiction: a review of preclinical studies

    OpenAIRE

    Schoenbaum, Geoffrey; Shaham, Yavin

    2007-01-01

    Studies using brain imaging methods have shown that neuronal activity in the orbitofrontal cortex, a brain area thought to promote the ability to control behavior according to likely outcomes or consequences, is altered in drug addicts. These human imaging findings have led to the hypothesis that core features of addiction like compulsive drug use and drug relapse are mediated in part by drug-induced changes in orbitofrontal function. Here, we discuss results from laboratory studies using rat...

  2. The Dopamine Hypothesis of Drug Addiction and Its Potential Therapeutic Value

    OpenAIRE

    Marco eDiana

    2011-01-01

    Dopamine (DA) transmission is deeply affected by drugs of abuse, and alterations in DA function are involved in the various phases of drug addiction and potentially exploitable therapeutically. In particular, basic studies have documented a reduction in the electrophysiological activity of DA neurons in alcohol, opiate, cannabinoid, and other drug-dependent rats. Further, DA release in the Nucleus accumbens (Nacc) is decreased in virtually all drug-dependent rodents. In parallel, these studie...

  3. Quantum Chemical Study on Structure-activity Relationship of Several Kinds of Drugs

    Institute of Scientific and Technical Information of China (English)

    LI Xiao-Hong; CHENG Xin-Lu; ZHANG Rui-Zhou; YANG Xiang-Dong

    2005-01-01

    The structure-activity relationship of several drugs with similar structure has been investigated by using ab initio method.The relation between the dipole moments and biological activities of these drugs was judged after comparing their geometric structures, dipole moments and inhibitory concentrations.In principle, new drug molecule could be reasonably designed by altering the place of groups and ultimately, the potential drug could be screened by comparing the dipole moments of obtained molecules.

  4. Altering prolactin concentrations in sows.

    Science.gov (United States)

    Farmer, C

    2016-07-01

    Prolactin has a multiplicity of actions, but it is of particular importance in gestating and lactating animals. In sows, it is involved in the control of mammary development and also holds essential roles in the lactogenic and galactopoietic processes. Furthermore, low circulating concentrations of prolactin are associated with the agalactia syndrome. The crucial role of prolactin makes it important to understand the various factors that can alter its secretion. Regulation of prolactin secretion is largely under the negative control of dopamine, and dopamine agonists consistently decrease prolactin concentrations in sows. On the other hand, injections of dopamine antagonists can enhance circulating prolactin concentrations. Besides pharmacologic agents, many other factors can also alter prolactin concentrations in sows. The use of Chinese-derived breeds, for instance, leads to increased prolactin concentrations in lactating sows compared with standard European white breeds. Numerous husbandry and feeding practices also have a potential impact on prolactin concentrations in sows. Factors, such as provision of nest-building material prepartum, housing at farrowing, high ambient temperature, stress, transient weaning, exogenous thyrotropin-releasing factor, exogenous growth hormone-releasing factor, nursing frequency, prolonged photoperiod, fasting, increased protein and/or energy intake, altered energy sources, feeding high-fiber diets, sorghum ergot or plant extracts, were all studied with respect to their prolactinemic properties. Although some of these practices do indeed affect circulating prolactin concentrations, none leads to changes as drastic as those brought about by dopamine agonists or antagonists. It appears that the numerous factors regulating prolactin concentrations in sows are still not fully elucidated, and that studies to develop novel applicable ways of increasing prolactin concentrations in sows are warranted.

  5. Altered Mental Status and Delirium.

    Science.gov (United States)

    Wilber, Scott T; Ondrejka, Jason E

    2016-08-01

    Older patients who present to the emergency department frequently have acute or chronic alterations of their mental status, including their level of consciousness and cognition. Recognizing both acute and chronic changes in cognition are important for emergency physicians. Delirium is an acute change in attention, awareness, and cognition. Numerous life-threatening conditions can cause delirium; therefore, prompt recognition and treatment are critical. The authors discuss an organized approach that can lead to a prompt diagnosis within the time constraints of the emergency department. PMID:27475019

  6. Acid Sulfate Alteration on Mars

    Science.gov (United States)

    Ming, D. W.; Morris, R. V.

    2016-01-01

    A variety of mineralogical and geochemical indicators for aqueous alteration on Mars have been identified by a combination of surface and orbital robotic missions, telescopic observations, characterization of Martian meteorites, and laboratory and terrestrial analog studies. Acid sulfate alteration has been identified at all three landing sites visited by NASA rover missions (Spirit, Opportunity, and Curiosity). Spirit landed in Gusev crater in 2004 and discovered Fe-sulfates and materials that have been extensively leached by acid sulfate solutions. Opportunity landing on the plains of Meridiani Planum also in 2004 where the rover encountered large abundances of jarosite and hematite in sedimentary rocks. Curiosity landed in Gale crater in 2012 and has characterized fluvial, deltaic, and lacustrine sediments. Jarosite and hematite were discovered in some of the lacustrine sediments. The high elemental abundance of sulfur in surface materials is obvious evidence that sulfate has played a major role in aqueous processes at all landing sites on Mars. The sulfate-rich outcrop at Meridiani Planum has an SO3 content of up to 25 wt.%. The interiors of rocks and outcrops on the Columbia Hills within Gusev crater have up to 8 wt.% SO3. Soils at both sites generally have between 5 to 14 wt.% SO3, and several soils in Gusev crater contain around 30 wt.% SO3. After normalization of major element compositions to a SO3-free basis, the bulk compositions of these materials are basaltic, with a few exceptions in Gusev crater and in lacustrine mudstones in Gale crater. These observations suggest that materials encountered by the rovers were derived from basaltic precursors by acid sulfate alteration under nearly isochemical conditions (i.e., minimal leaching). There are several cases, however, where acid sulfate alteration minerals (jarosite and hematite) formed in open hydrologic systems, e.g., in Gale crater lacustrine mudstones. Several hypotheses have been suggested for the

  7. Drug: D06732 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available r component: Loganin [CPD:C01433] Powdered product: Standards for non-pharmacopoeial crude drugs Therapeutic category of drugs... in Japan [BR:br08301] 5 Crude drugs and Chinese medicine formulations 51 Crude drugs 510 Crude drugs...ine in Japan [BR:br08304] Crude Drugs Drugs for Qi Drugs for replenishing Qi D06732 Cornus fruit; Sanshuyu Crude drugs... 5100 Crude drugs D06732 Cornus fruit (JP16) Traditional Chinese Medic

  8. The antihelmintic drug pyrvinium pamoate targets aggressive breast cancer.

    Directory of Open Access Journals (Sweden)

    Wei Xu

    Full Text Available WNT signaling plays a key role in the self-renewal of tumor initiation cells (TICs. In this study, we used pyrvinium pamoate (PP, an FDA-approved antihelmintic drug that inhibits WNT signaling, to test whether pharmacologic inhibition of WNT signaling can specifically target TICs of aggressive breast cancer cells. SUM-149, an inflammatory breast cancer cell line, and SUM-159, a metaplastic basal-type breast cancer cell line, were used in these studies. We found that PP inhibited primary and secondary mammosphere formation of cancer cells at nanomolar concentrations, at least 10 times less than the dose needed to have a toxic effect on cancer cells. A comparable mammosphere formation IC50 dose to that observed in cancer cell lines was obtained using malignant pleural effusion samples from patients with IBC. A decrease in activity of the TIC surrogate aldehyde dehydrogenase was observed in PP-treated cells, and inhibition of WNT signaling by PP was associated with down-regulation of a panel of markers associated with epithelial-mesenchymal transition. In vivo, intratumoral injection was associated with tumor necrosis, and intraperitoneal injection into mice with tumor xenografts caused significant tumor growth delay and a trend toward decreased lung metastasis. In in vitro mammosphere-based and monolayer-based clonogenic assays, we found that PP radiosensitized cells in monolayer culture but not mammosphere culture. These findings suggest WNT signaling inhibition may be a feasible strategy for targeting aggressive breast cancer. Investigation and modification of the bioavailability and toxicity profile of systemic PP are warranted.

  9. Assessing Specificity of Anticancer Drugs In Vitro.

    Science.gov (United States)

    Kluwe, Lan

    2016-01-01

    A procedure for assessing specificity of anticancer drugs in vitro using cultures containing both tumor and non-tumor cells is demonstrated. The key element is the quantitative determination of a tumor-specific genetic alteration in relation to a universal sequence using a dual-probe digital PCR assay and the subsequent calculation of the proportion of tumor cells. The assay is carried out on a culture containing tumor cells of an established line and spiked-in non-tumor cells. The mixed culture is treated with a test drug at various concentrations. After the treatment, DNA is prepared directly from the survived adhesive cells in wells of 96-well plates using a simple and inexpensive method, and subjected to a dual-probe digital PCR assay for measuring a tumor-specific genetic alteration and a reference universal sequence. In the present demonstration, a heterozygous deletion of the NF1 gene is used as the tumor-specific genetic alteration and a RPP30 gene as the reference gene. Using the ratio NF1/RPP30, the proportion of tumor cells was calculated. Since the dose-dependent change of the proportion of tumor cells provides an in vitro indication for specificity of the drug, this genetic and cell-based in vitro assay will likely have application potential in drug discovery. Furthermore, for personalized cancer-care, this genetic- and cell-based tool may contribute to optimizing adjuvant chemotherapy by means of testing efficacy and specificity of candidate drugs using primary cultures of individual tumors. PMID:27078035

  10. Psychostimulant Drugs and Neuroplasticity

    Directory of Open Access Journals (Sweden)

    Emilio Fernandez-Espejo

    2011-06-01

    Full Text Available Drugs of abuse induce plastic changes in the brain that seem to underlie addictive phenomena. These plastic changes can be structural (morphological or synaptic (biochemical, and most of them take place in the mesolimbic and mesostriatal circuits. Several addiction-related changes in brain circuits (hypofrontality, sensitization, tolerance as well as the outcome of treatment have been visualized in addicts to psychostimulants using neuroimaging techniques. Repeated exposure to psychostimulants induces morphological changes such as increase in the number of dendritic spines, changes in the morphology of dendritic spines, and altered cellular coupling through new gap junctions. Repeated exposure to psychostimulants also induces various synaptic adaptations, many of them related to sensitization and neuroplastic processes, that include up- or down-regulation of D1, D2 and D3 dopamine receptors, changes in subunits of G proteins, increased adenylyl cyclase activity, cyclic AMP and protein kinase A in the nucleus accumbens, increased tyrosine hydroxylase enzyme activity, increased calmodulin and activated CaMKII in the ventral tegmental area, and increased deltaFosB, c-Fos and AP-1 binding proteins. Most of these changes are transient, suggesting that more lasting plastic brain adaptations should take place. In this context, protein synthesis inhibitors block the development of sensitization to cocaine, indicating that rearrangement of neural networks must develop for the long-lasting plasticity required for addiction to occur. Self-administration studies indicate the importance of glutamate neurotransmission in neuroplastic changes underlying transition from use to abuse. Finally, plastic changes in the addicted brain are enhanced and aggravated by neuroinflammation and neurotrophic disbalance after repeated psychostimulants.

  11. The Potential of Silk and Silk-Like Proteins as Natural Mucoadhesive Biopolymers for Controlled Drug Delivery

    OpenAIRE

    Brooks, Amanda E.

    2015-01-01

    Drug delivery across mucus membranes is a particularly effective route of administration due to the large surface area. However, the unique environment present at the mucosa necessitates altered drug formulations designed to (1) deliver sensitive biologic molecules, (2) promote intimate contact between the mucosa and the drug, and (3) prolong the drug's local residence time. Thus, the pharmaceutical industry has an interest in drug delivery systems formulated around the use of mucoadhesive po...

  12. Drugs and drug policy in the Netherlands

    NARCIS (Netherlands)

    Leuw, Ed.

    1991-01-01

    The Dutch parliament enacted the revised Opium Act in 1976. This penal law is part of the Dutch drug policy framework that includes tolerance for nonconforming lifestyles, risk reduction in regard to the harmful health and social consequences of drug taking, and penal measures directed against illeg

  13. NEW DRUG DELIVERY SYSTEM

    Directory of Open Access Journals (Sweden)

    Sarkar Biresh K

    2011-05-01

    Full Text Available Incorporating an existing medicine into a new drug delivery system can significantly improve its performance in terms of efficacy, safety, and improved patient compliance. The need for delivering drugs to patients efficiently and with fewer side effects has prompted pharmaceutical companies to engage in the development of new drug delivery systems. Today, drug delivery companies are engaged in the development of multiple platform technologies for controlled release, delivery of large molecules, liposome, taste-masking, oral fast- dispersing dosage forms, technology for in- soluble drugs, and delivery of drugs through intranasal, pulmonary, transdermal, vaginal, colon, and transmucosal routes.

  14. Antiepileptic drugs: newer targets and new drugs

    Directory of Open Access Journals (Sweden)

    Vihang S. Chawan

    2016-06-01

    Full Text Available Epilepsy is a common neurological disorder affecting 0.5-1% of the population in India. Majority of patients respond to currently available antiepileptic drugs (AEDs, but a small percentage of patients have shown poor and inadequate response to AEDs in addition to various side effects and drug interactions while on therapy. Thus there is a need to develop more effective AEDs in drug resistant epilepsy which have a better safety profile with minimal adverse effects. The United States food and drug administration (USFDA has approved eslicarbazepine acetate, ezogabine, perampanel and brivaracetam which have shown a promising future as better AEDs and drugs like ganaxolone, intranasal diazepam, ICA- 105665, valnoctamide, VX-765, naluzotan are in the pipeline. [Int J Basic Clin Pharmacol 2016; 5(3.000: 587-592

  15. TWO STAGE FRAMEWORK FOR ALTERED FINGERPRINT MATCHING

    OpenAIRE

    T. R. Anoop; M.G. Mini

    2015-01-01

    Fingerprint alteration is the process of masking one’s identity from personal identification systems especially in boarder control security systems. Failure of matching the altered fingerprint of the criminals against the watch list of fingerprints can help them to break the security system. This fact leads to the need of a method for altered fingerprint matching. This paper presents a two stage method for altered fingerprint matching. In first stage, approximated global ridge orientation fie...

  16. Identifying mechanistic similarities in drug responses

    KAUST Repository

    Zhao, C.

    2012-05-15

    Motivation: In early drug development, it would be beneficial to be able to identify those dynamic patterns of gene response that indicate that drugs targeting a particular gene will be likely or not to elicit the desired response. One approach would be to quantitate the degree of similarity between the responses that cells show when exposed to drugs, so that consistencies in the regulation of cellular response processes that produce success or failure can be more readily identified.Results: We track drug response using fluorescent proteins as transcription activity reporters. Our basic assumption is that drugs inducing very similar alteration in transcriptional regulation will produce similar temporal trajectories on many of the reporter proteins and hence be identified as having similarities in their mechanisms of action (MOA). The main body of this work is devoted to characterizing similarity in temporal trajectories/signals. To do so, we must first identify the key points that determine mechanistic similarity between two drug responses. Directly comparing points on the two signals is unrealistic, as it cannot handle delays and speed variations on the time axis. Hence, to capture the similarities between reporter responses, we develop an alignment algorithm that is robust to noise, time delays and is able to find all the contiguous parts of signals centered about a core alignment (reflecting a core mechanism in drug response). Applying the proposed algorithm to a range of real drug experiments shows that the result agrees well with the prior drug MOA knowledge. © The Author 2012. Published by Oxford University Press. All rights reserved.

  17. IMPROVING ACCESS TO DRUGS

    Directory of Open Access Journals (Sweden)

    Max Joseph Herman

    2012-11-01

    Full Text Available Although essentially not all therapies need drug intervention, drugs is still an important components in health sector, either in preventive, curative, rehabilitative or promotion efforts. Hence the access to drugs is a main problem, either in international or national scale even to the smallest unit. The problem on access to drugs is very complicated and cannot be separated especially from pharmacy management problems; moreover in general from the overall lack of policy development and effective of health policy, and also the implementation process. With the policy development and effective health policy, rational drug uses, sufficient health service budget so a country can overcome the health problems. Besides infrastructures, regulations, distribution and cultural influences; the main obstacles for drug access is drugs affordability if the price of drugs is an important part and determined by many factors, especially the drug status whether is still patent orgenerics that significantly decrease cost of health cares and enhance the drugs affordability. The determination of essential drug prices in developing countries should based on equity principal so that poor people pay cheaper and could afford the essential drugs. WHO predicts two third of world population can not afford the essential drugs in which in developing countries, some are because of in efficient budget allocation in consequence of drug distribution management, including incorrect selection and allocation and also irrational uses. In part these could be overcome by enhancing performances on the allocation pharmacy needs, including the management of information system, inventory management, stock management and the distribution. Key words: access, drugs, essential drugs, generic drugs

  18. Rational Use of Drugs: Pharmaceutical Aspects of the Drug Selection

    OpenAIRE

    Natalya B. Rostova, PhD, ScD; Tatiana F. Odegova, PhD, ScD

    2012-01-01

    In this article, the problems encountered in the rational use of drugs are discussed, one of the areas of optimization of drug supply being the rational choice of drugs, particularly, a regulatory activity regarding the approach to the selection of standardized drug lists (drug formulary) for public drug supply, according to government guarantees and programs. The clinical aspects of the drug selection are expounded in detail. The characteristics of the drugs (original or generic drug (generi...

  19. Assessment of potential drug-drug interactions and its associated factors in the hospitalized cardiac patients.

    Science.gov (United States)

    Murtaza, Ghulam; Khan, Muhammad Yasir Ghani; Azhar, Saira; Khan, Shujaat Ali; Khan, Tahir M

    2016-03-01

    Drug-drug interactions (DDIs) may result in the alteration of therapeutic response. Sometimes they may increase the untoward effects of many drugs. Hospitalized cardiac patients need more attention regarding drug-drug interactions due to complexity of their disease and therapeutic regimen. This research was performed to find out types, prevalence and association between various predictors of potential drug-drug interactions (pDDIs) in the Department of Cardiology and to report common interactions. This study was performed in the hospitalized cardiac patients at Ayub Teaching Hospital, Abbottabad, Pakistan. Patient charts of 2342 patients were assessed for pDDIs using Micromedex® Drug Information. Logistic regression was applied to find predictors of pDDIs. The main outcome measure in the study was the association of the potential drug-drug interactions with various factors such as age, gender, polypharmacy, and hospital stay of the patients. We identified 53 interacting-combinations that were present in total 5109 pDDIs with median number of 02 pDDIs per patient. Overall, 91.6% patients had at least one pDDI; 86.3% were having at least one major pDDI, and 84.5% patients had at least one moderate pDDI. Among 5109 identified pDDIs, most were of moderate (55%) or major severity (45%); established (24.2%), theoretical (18.8%) or probable (57%) type of scientific evidence. Top 10 common pDDIs included 3 major and 7 moderate interactions. Results obtained by multivariate logistic regression revealed a significant association of the occurrence of pDDIs in patient with age of 60 years or more (p Older patients, patients with longer hospital stay and with elevated number of prescribed drugs were at higher risk of pDDIs. PMID:27013915

  20. Pharmacogenomics in clinical drug development and potential for alopecia areata.

    Science.gov (United States)

    Warner, Amelia W

    2013-12-01

    Alopecia areata, alopecia totalis, and alopecia universalis likely represent a constellation of related diseases with similar, yet distinct heritability markers. There is currently no known curative therapy that works universally for all patients. Pharmacogenomic research enables the pharmaceutical industry to understand variability of patient responses to drugs during clinical drug development and during post-marketing surveillance. Understanding the genetic basis for patient response/non-response can enable the development of individualized therapies for those patients with an inherited basis for altered response to drug therapy. There are multiple examples of drugs that now contain a recommendation for genetic testing before dosing in their drug labels, directing clinicians to obtain genetic information for each individual patient in order to help direct drug therapy. PMID:24326549

  1. Pharmacokinetics of drugs in cachectic patients: a systematic review.

    Directory of Open Access Journals (Sweden)

    Katja Trobec

    Full Text Available Cachexia is a weight-loss process caused by an underlying chronic disease such as cancer, chronic heart failure, chronic obstructive pulmonary disease, or rheumatoid arthritis. It leads to changes in body structure and function that may influence the pharmacokinetics of drugs. Changes in gut function and decreased subcutaneous tissue may influence the absorption of orally and transdermally applied drugs. Altered body composition and plasma protein concentration may affect drug distribution. Changes in the expression and function of metabolic enzymes could influence the metabolism of drugs, and their renal excretion could be affected by possible reduction in kidney function. Because no general guidelines exist for drug dose adjustments in cachectic patients, we conducted a systematic search to identify articles that investigated the pharmacokinetics of drugs in cachectic patients.

  2. Nanosuspension: An approach to enhance solubility of drugs

    Directory of Open Access Journals (Sweden)

    Vishal R Patel

    2011-01-01

    Full Text Available One of the major problems associated with poorly soluble drugs is very low bioavailability. The problem is even more complex for drugs like itraconazole, simvastatin, and carbamazepine which are poorly soluble in both aqueous and nonaqueous media, belonging to BCS class II as classified by biopharmaceutical classification system. Formulation as nanosuspension is an attractive and promising alternative to solve these problems. Nanosuspension consists of the pure poorly water-soluble drug without any matrix material suspended in dispersion. Preparation of nanosuspension is simple and applicable to all drugs which are water insoluble. A nanosuspension not only solves the problems of poor solubility and bioavailability, but also alters the pharmacokinetics of drug and thus improves drug safety and efficacy. This review article describes the preparation methods, characterization, and applications of the nanosuspension.

  3. Transcription factors as targets of anticancer drugs.

    Science.gov (United States)

    Gniazdowski, M; Czyz, M

    1999-01-01

    Several general and gene- and cell-selective transcription factors are required for specific transcription to occur. Many of them exert their functions through specific contacts either in the promoter region or at distant sequences regulating the initiation. These contacts may be altered by anticancer drugs which form non-covalent complexes with DNA. Covalent modifications of DNA by alkylating agents may prevent transcription factors from recognizing their specific sequences or may constitute multiple "unnatural" binding sites in DNA which attract the factors thus decreasing their availability in the cell. The anticancer drug-transcription factor interplay which is based on specific interactions with DNA may contribute to pharmacological properties of the former and provide a basis for the search for new drugs. PMID:10547027

  4. Drug Facts: Anabolic Steroids

    Science.gov (United States)

    ... Share Print Home » Publications » DrugFacts » Anabolic Steroids DrugFacts: Anabolic Steroids Email Facebook Twitter Revised March 2016 What are anabolic steroids? Anabolic steroids are synthetic variations of the male ...

  5. Drugs@FDA Database

    Data.gov (United States)

    U.S. Department of Health & Human Services — Information about FDA-approved brand name and generic prescription and over-the-counter human drugs and biological therapeutic products. Drugs@FDA includes most of...

  6. Drug use first aid

    Science.gov (United States)

    ... or extreme social withdrawal. Cannabis drugs such as marijuana may cause relaxation, impaired motor skills, and increased appetite. When prescription drugs are taken in higher than normal amounts, serious side effects may occur.

  7. Prescription Drug Profiles PUF

    Data.gov (United States)

    U.S. Department of Health & Human Services — This release contains the Prescription Drug Profiles Public Use Files (PUFs) drawn from Medicare prescription drug claims for the year of the date on which the...

  8. Street Drugs and Pregnancy

    Science.gov (United States)

    ... and premature birth Zika virus and pregnancy Microcephaly Medicine safety and pregnancy Birth defects prevention Learn how ... Is it safe? > Street drugs and pregnancy Street drugs and pregnancy E-mail to a friend Please ...

  9. Drugs to be Discontinued

    Data.gov (United States)

    U.S. Department of Health & Human Services — Companies are required under Section 506C of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (as amended by the Food and Drug Administration Safety and...

  10. Food and Drug Administration

    Science.gov (United States)

    ... Drugs @ FDA Device Approvals & Clearances Biologics Products & Establishments Food & Color Additives Animal Drugs @ FDA MedWatch: Adverse Event Reporting Report a Non-Emergency For Industry: Reportable Food Registry Report an Emergency Report Suspected Criminal Activity ...

  11. Prescription Drug Abuse

    Science.gov (United States)

    ... what the doctor prescribed, it is called prescription drug abuse. It could be Taking a medicine that ... purpose, such as getting high Abusing some prescription drugs can lead to addiction. These include narcotic painkillers, ...

  12. Life after Drugs

    Institute of Scientific and Technical Information of China (English)

    LIUDONGPING

    2004-01-01

    THE famous Kunming Drug Rehabilitation Center, founded in 1989, is located in the suburbs of Kunming City. Yunnan Province. It is the first drug rehabilitation center in China and the biggest in Asia.Covering 200 hectares, the center is

  13. Intra-Tumoral Heterogeneity Assessment Model in 18 F-FDG PET Images%18F-FDG PET图像中肿瘤非均匀性评估模型

    Institute of Scientific and Technical Information of China (English)

    冯远明; 李崇崇; 张珺; 王平

    2013-01-01

    肿瘤在功能图像中表现出的非均匀特性能够一定程度上反应出其基本特性和对治疗的响应,对这一特性的数学描述和建模可为治疗和预估治疗效果提供有意义的量化参考数据.本文提出一种新的放射性同位素氟18标记的脱氧葡萄糖(18 F-FDG)正电子发射断层影像(PET)中肿瘤内部非均匀性计算模型,通过图像中相邻像素的FDG标准摄取值(SUV)差异和其位置特征,可得出能描述肿瘤图像呈现的非均匀特性的参数H指数.使用矩形和高斯球模体以及3例肺癌患者数据,通过与灰度共生矩阵(GLCM)图像分析法比较研究,验证了该模型的有效性.%The intra-tumoral heterogeneity information of cancers from functional images can reflect their basic characteristics and responses to treatment.Mathematical illustration and modeling of this characteristic will provide effective ways for the quantitative analysis of the responses.A new model is proposed to assess tumor heterogeneity by summing up the voxel-wise distribution of differential standard uptake value (SUV) of fluorodeoxyglucose (FDG) from the 18 F-FDG positron emission tomography (PET) image data.Based on square testing graphics,spherical phantoms and the 18F-FDG PET image data of 3 lung cancer patients,the new model with the H index was compared with a widely-used model of gray level co-occurrence matrix (GLCM) for image texture characterization,thus verifying its effectiveness.

  14. NANOTECHNOLOGY: A PROMISING CARRIER FOR INTRACELLULAR DRUG DELIVERY SYSTEM

    OpenAIRE

    Malakar Jadupati; Ghosh Amitava; Basu Aalok; Nayak Amit Kumar

    2012-01-01

    Nanotechnology is on its way to make a big impact in Biotech, Pharmaceutical and Medical diagnostics sciences. Nanotechnology holds a tremendous potential when it applied in the fields of drug delivery. In this review it has been discussed how nanotechnology can implemented to design formulations which can effectively carry drug molecule to the targeted cell organelles. Introduction of certain functional groups or addition of surface active agents may alter the characteristics of the carrier ...

  15. Androgen receptor: structure, role in prostate cancer and drug discovery

    OpenAIRE

    Tan, MH Eileen; Li, Jun; Xu, H. Eric; Melcher, Karsten; Yong, Eu-Leong

    2014-01-01

    Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2–3 years as the patients develop castration-resistant prostate cancer ...

  16. [Drugs during pregnancy--effects on the mother and next generation].

    Science.gov (United States)

    Slamberová, R

    2003-02-01

    Drug abuse during pregnancy is a growing problem in all developed countries of the world. Drug-abusing women have irregular menstrual cycle often resulting in amenorrhea. However, the irregular cycle does not mean that the drug-abusing women cannot become pregnant and in that case they expose to the effects of the drug not only themselves but also their fetus. The drug easily crosses the placental barrier into the fetal body and to the maternal milk and affects both pre- and postnatal development of the child. After the cessation of the drug exposure the child has similar withdrawal symptoms as drug-abusing adults. Maternal drug abuse affects the developing system and its long-term effects can persist till adulthood. It was demonstrated that prenatal drug exposure (to drugs such as cocaine, metamphetamine, heroin, and morphine) decreases the weight of the newborns and decreases the rate of their maturation. Prenatal drug exposure also impairs learning and memory, alters responses to the new environment and stressors, changes seizure susceptibility and sexual behavior of the adult progeny. These effects seem to be due to alterations in neurotransmitter systems in the central nervous system affected by the prenatal drug exposure. The best known therapy is prevention and an attempt to diminish the drug abuse especially during pregnancy. This would be a solution not only for the issues raised in this article but for the drug abuse problem in general as well.

  17. Drug: D06911 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available ude drugs 510 Crude drugs 5100 Crude drugs D06911 Lilium bulb (JP16) Traditional Chinese Medicine in Japan [BR:br08304] Crude Drugs... Drugs for replenishing Ying Drugs for replenishing Ying D06911 *Lilii bulbus; Lily bulb; Byakugo Drugs

  18. Drug: D06688 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available ese Medicine in Japan [BR:br08304] Crude Drugs Drugs for clearing heat Drugs for clearing heat D06688 *Scute...eal drugs Stomachic and antidiarrheal drugs D06688 *Scutellaria root; Powdered scutellaria root; Scutellaria root Drugs... for pus discharge Drugs for pus discharge D06688 *Scutellaria root; Powdered scutellaria root; S

  19. Drug: D06718 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available ied) Major component: Ginsenoside [CPD:C08944 C08945] Powdered product: Standards for non-pharmacopoeial crude drugs... Therapeutic category of drugs in Japan [BR:br08301] 5 Crude drugs and Chinese medicine formulations 51 Crude drugs... 510 Crude drugs 5100 Crude drugs D06718 Red ginseng (JP16) Crude drugs

  20. Drug: D06680 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available eaf Therapeutic category of drugs in Japan [BR:br08301] 5 Crude drugs and Chinese medicine formulations 51 Crude drugs 510 Crude drug...s 5100 Crude drugs D06680 Sweet hydrangea leaf (JP16); Powdered sweet hydrangea leaf (JP16) Crude drugs

  1. Drug: D06907 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available s family) Bambusa tuldoides, Phyllostachys nigra, Phyllostachys bambusoides culm; Standards for non-pharmacopoeial crude drugs... Therapeutic category of drugs in Japan [BR:br08301] 5 Crude drugs... and Chinese medicine formulations 51 Crude drugs 510 Crude drugs 5100 Crude drugs D06907 Bamboo culm (no...nd expectorants D06907 Bambusae caulis; Phyllostachysis caulis; Tikujyo Crude drugs

  2. Drug: D06780 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D06780 Crude, Drug Atractylodes rhizome (JP16); Powdered atractylodes rhizome (JP16... drugs 510 Crude drugs 5100 Crude drugs D06780 Atractylodes rhizome (JP16); Powder...pness Diuretic drugs D06780 *Atractylodes rhizome; Powdered atractylodes rhizome; Atractyloides rhizoma Drug...s for resolving dampness D06780 *Atractylodes rhizome; Powdered atractylodes rhizome; Atractyloides rhizoma

  3. Drug: D06798 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available R:br08301] 5 Crude drugs and Chinese medicine formulations 51 Crude drugs 510 Crude drugs 5100 Crude drugs D...06798 Coix seed (JP16); Powdered coix seed (JP16) 59 Other crude drugs and Chinese medicine formula...tions 590 Other crude drugs and Chinese medicine formulations 5900 Other crude drugs and Chinese medicine formula

  4. NEW DRUG DELIVERY SYSTEM

    OpenAIRE

    Sarkar Biresh K; Jain Devananda; Banerjee Angshu

    2011-01-01

    Incorporating an existing medicine into a new drug delivery system can significantly improve its performance in terms of efficacy, safety, and improved patient compliance. The need for delivering drugs to patients efficiently and with fewer side effects has prompted pharmaceutical companies to engage in the development of new drug delivery systems. Today, drug delivery companies are engaged in the development of multiple platform technologies for controlled release, delivery of large molecule...

  5. Drugs in sport

    OpenAIRE

    Mottram, David R

    2012-01-01

    This new edition includes fresh information regarding drugs use and abuse in sport and the updated worldwide anti-doping laws, and changes to the prohibited and therapeutic use exemption lists. The objectives of the book are to review/discuss the latest information on drugs in sport by considering i) actions of drugs and hormones, ii) medication and nutritional supplements in sport, iii) the latest doping control regulations of the WADA, iv) the use of banned therapeutic drugs in sport, v) an...

  6. Medicinsk forbedring: study drugs

    OpenAIRE

    Holm Sørensen, Camilla; Juul Asmussen, Melanie; Constantin, Liv; Haugtved, Claire Rigmor

    2015-01-01

    This study investigates medical optimization regarding cognitive enhancement. Study drugs are performance-enhancing drugs that people use in terms of optimizing cognitive skills. The use of study drugs has turned out to have a beneficial effect when it comes to perform in stressful situations for example an examination. The purpose of our project is to analyze central arguments for and against the use of study drugs. We analyze two arguments for and three arguments that express a statem...

  7. IMPROVING ACCESS TO DRUGS

    OpenAIRE

    Max Joseph Herman

    2012-01-01

    Although essentially not all therapies need drug intervention, drugs is still an important components in health sector, either in preventive, curative, rehabilitative or promotion efforts. Hence the access to drugs is a main problem, either in international or national scale even to the smallest unit. The problem on access to drugs is very complicated and cannot be separated especially from pharmacy management problems; moreover in general from the overall lack of policy development and effec...

  8. Rational Use of Drugs: Pharmaceutical Aspects of the Drug Selection

    Directory of Open Access Journals (Sweden)

    Natalya B. Rostova, PhD, ScD

    2012-09-01

    Full Text Available In this article, the problems encountered in the rational use of drugs are discussed, one of the areas of optimization of drug supply being the rational choice of drugs, particularly, a regulatory activity regarding the approach to the selection of standardized drug lists (drug formulary for public drug supply, according to government guarantees and programs. The clinical aspects of the drug selection are expounded in detail. The characteristics of the drugs (original or generic drug (generics, the origin of drugs and the breadth of therapeutic index, have been taken into account. Certain stages have been analyzed, particularly drug use in individual diseases, drug selection, expert drug evaluation, and expert recommendations to include specific drugs in the drug list. Organizational steps have been proposed to implement the rational choice of drugs to be included in the drug formulary.

  9. Genetic alterations in pancreatic carcinoma

    Directory of Open Access Journals (Sweden)

    Schmid Roland M

    2003-01-01

    Full Text Available Abstract Cancer of the exocrine pancreas represents the fifth leading cause of cancer death in the Western population with an average survival after diagnosis of 3 to 6 months and a five-year survival rate under 5%. Our understanding of the molecular carcinogenesis has improved in the last few years due to the development of novel molecular biological techniques. Pancreatic cancer is a multi-stage process resulting from the accumulation of genetic changes in the somatic DNA of normal cells. In this article we describe major genetic alterations of pancreatic cancer, mutations in the proto-oncogene K-RAS and the tumor suppressors INK4A, TP53 and DPC4/SMAD4. The accumulation of these genetic changes leads to a profound disturbance in cell cycle regulation and continuous growth. The knowledge of the underlying molecular mechanisms will offer new therapeutic and diagnostic options and hopefully improve the outcome of this aggressive disease.

  10. Genetic alterations in pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Muhammad Wasif Saif; Lena Karapanagiotou; Kostas Syrigos

    2007-01-01

    The diagnosis of pancreatic cancer is devastating for patients and their relatives as the incidence rate is approximately the same as mortality rate. Only a small percentage, which ranges from 0.4% to 4% of patients who have been given this diagnosis, will be alive at five years. At the time of diagnosis, 80% of pancreatic cancer patients have unresectable or metastatic disease.Moreover, the therapeutic alternatives offered by chemotherapy or radiotherapy are few, if not zero. For all these reasons, there is an imperative need of analyzing and understanding the primitive lesions that lead to invasive pancreatic adenocarcinoma. Molecular pathology of these lesions is the key of our understanding of the mechanisms underlying the development of this cancer and will probably help us in earlier diagnosis and better therapeutic results. This review focuses on medical research on pancreatic cancer models and the underlying genetic alterations.

  11. Effects of drugs on mucus clearance.

    Science.gov (United States)

    Houtmeyers, E; Gosselink, R; Gayan-Ramirez, G; Decramer, M

    1999-08-01

    Mucociliary clearance (MCC), the process in which airway mucus together with substances trapped within are moved out of the lungs, is an important defence mechanism of the human body. Drugs may alter this process, such that it is necessary to know the effect of the drugs on MCC. Indeed, agents stimulating MCC may be used therapeutically in respiratory medicine, especially in patients suspected of having an impairment of their mucociliary transport system. In contrast, caution should be taken with drugs depressing MCC as an undesired side-effect, independently of their therapeutic indication. Since cough clearance (CC) serves as a back-up system when MCC fails, the influence of drugs must be examined not only on MCC but also on CC. Ultimately, the clinical repercussions of alterations in mucus transport induced by drug administration must be studied. Tertiary ammonium compounds (anticholinergics), aspirin, anaesthetic agents and benzodiazepines have been shown to be capable of depressing the mucociliary transport system. Cholinergics, methylxanthines, sodium cromoglycate, hypertonic saline, saline as well as water aerosol have been shown to increase MCC. Adrenergic antagonists, guaifenesin, S-carboxymethylcysteine, sodium 2-mercapto-ethane sulphonate and frusemide have been reported not to alter the mucociliary transport significantly. Amiloride, uridine 5'-triphosphate (UTP), quaternary ammonium compounds (anticholinergics), adrenergic agonists, corticosteroids, recombinant human deoxyribonuclease (rhDNase), N-acetylcysteine, bromhexine and ambroxol have been reported either not to change or to augment MCC. Indirect data suggest that surfactant as well as antibiotics may improve the mucociliary transport system. As for the influence of drugs on CC, amiloride and rhDNase have been demonstrated to increase the effectiveness of cough. A trend towards an improved CC was noted after treatment with adrenergic agonists. The anticholinergic agent ipratropium bromide, which

  12. Writing Drug Cultures

    DEFF Research Database (Denmark)

    Nissen, Morten

    2012-01-01

    The paper juxtaposes the cultural mediation of experience through drugs with that performed with text. As a sample of the currently radically changing relations between professional and lay knowledge in the field of drug interventions, the website of a Copenhagen institution for young drug users ...

  13. Drug: D06741 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available :C17056] Therapeutic category of drugs in Japan [BR:br08301] 5 Crude drugs and Chinese medicine formulations 51 Crude drugs... 510 Crude drugs 5100 Crude drugs D06741 Plantago herb (JP16) Trad...itional Chinese Medicine in Japan [BR:br08304] Crude Drugs Drugs for dampness Diuretic drugs D06741 Plantago... herb; Plantago herb Crude drugs [BR:br08305] Dicot plants: asterids Plantaginaceae (plantain family) D06741 Plantago herb PubChem: 47208392 ...

  14. Drug: D06707 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available ategory: 5100 Apiaceae (carrot family) Notopterygium rhizome Therapeutic category of drugs in Japan [BR:br08301] 5 Crude drugs... and Chinese medicine formulations 51 Crude drugs 510 Crude drugs 5100 Crude drugs D06707 ...rude Drugs Diaphoretic drugs Diaphoretic drugs pungent in flavor and warm in property D06707 Notopterygium rhizome Crude drugs...Notopterygium rhizome (JP16) Traditional Chinese Medicine in Japan [BR:br08304] C

  15. Drug: D06734 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available buckthorn family) Jujube seed Major component: Zizybeoside [CPD:C17564 C17565] Therapeutic category of drugs... in Japan [BR:br08301] 5 Crude drugs and Chinese medicine formulations 51 Crude drugs 510 Crude drugs 5100 Crude drugs...08304] Crude Drugs Drugs for Qi Sedative drugs D06734 Jujube seed Crude drugs [BR:br08305] Dicot plants: rosids Rhamnaceae (buckthorn family) D06734 Jujube seed PubChem: 47208385 ...

  16. Drug: D06909 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available data rhizome Therapeutic category of drugs in Japan [BR:br08301] 5 Crude drugs an...d Chinese medicine formulations 51 Crude drugs 510 Crude drugs 5100 Crude drugs D06909 Aralia rhizome (JP16)... Traditional Chinese Medicine in Japan [BR:br08304] Crude Drugs Drugs for dampness Antirheumatic drugs D0690...9 Araliae cardatae rhizoma; Dokkatsu Crude drugs [BR:br08305] Dicot plants: asterids Araliaceae (ginseng family) D06909 Aralia rhizome PubChem: 51091251 ...

  17. Drug: D06715 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available ory family) Pharbitis seed Major component: Pharbitin Therapeutic category of drugs... in Japan [BR:br08301] 5 Crude drugs and Chinese medicine formulations 51 Crude drugs 510 Crude drugs 5100 Crude drugs... D06715 Pharbitis seed (JP16) Traditional Chinese Medicine in Japan [BR:br08304] Crude Drugs Purgative drugs... Purgative drugs D06715 Pharbitis seed; Pharbitis seed Crude drugs [B

  18. Drug: D06783 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available [CPD:C14495] Therapeutic category of drugs in Japan [BR:br08301] 5 Crude drugs an...d Chinese medicine formulations 51 Crude drugs 510 Crude drugs 5100 Crude drugs D06783 Poria sclerotium (JP1...6); Powdered poria sclerotium (JP16) Traditional Chinese Medicine in Japan [BR:br08304] Crude Drugs Drugs for dampness Diuretic drugs... D06783 Poria sclerotium; Powdered poria sclerotium; Hoelen Crude drugs

  19. Drug: D06723 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available ponent: Palmitic acid [CPD:C00249] Therapeutic category of drugs in Japan [BR:br08301] 5 Crude drugs and Chi...nese medicine formulations 51 Crude drugs 510 Crude drugs 5100 Crude drugs D06723... Burdock fruit (JP16) Traditional Chinese Medicine in Japan [BR:br08304] Crude Drugs Diaphoretic drugs Diaphoretic drugs... pungent in flavor and cool in property D06723 Burdock fruit Crude drugs [BR:br08305] Dicot plan

  20. Drug: D06765 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available ponent: Vanillyl alcohol [CPD:C06317] Therapeutic category of drugs in Japan [BR:br08301] 5 Crude drugs and ...Chinese medicine formulations 51 Crude drugs 510 Crude drugs 5100 Crude drugs D06765 Gastrodia tuber (JP16) ...Traditional Chinese Medicine in Japan [BR:br08304] Crude Drugs Drugs for Qi Sedative drugs... D06765 Gastrodia tuber; Tianma Crude drugs [BR:br08305] Monocot plants Orchidaceae (orchid family) D06765 Gastrodia tuber PubChem: 47208416 ...