21 CFR 500.86 - Marker residue and target tissue.

Code of Federal Regulations, 2014 CFR

2014-04-01

...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS GENERAL Regulation of Carcinogenic Compounds Used in Food-Producing Animals § 500.86 Marker residue and target tissue. (a) For each edible tissue, the sponsor shall... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Marker residue and target tissue. 500.86 Section...

21 CFR 500.86 - Marker residue and target tissue.

Code of Federal Regulations, 2013 CFR

2013-04-01

...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS GENERAL Regulation of Carcinogenic Compounds Used in Food-Producing Animals § 500.86 Marker residue and target tissue. (a) For each edible tissue, the sponsor shall... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Marker residue and target tissue. 500.86 Section...

Photon beam dose distributions for patients with implanted temporary tissue expanders

NASA Astrophysics Data System (ADS)

Asena, A.; Kairn, T.; Crowe, S. B.; Trapp, J. V.

2015-01-01

This study examines the effects of temporary tissue expanders (TTEs) on the dose distributions of photon beams in breast cancer radiotherapy treatments. EBT2 radiochromic film and ion chamber measurements were taken to quantify the attenuation and backscatter effects of the inhomogeneity. Results illustrate that the internal magnetic port present in a tissue expander causes a dose reduction of approximately 25% in photon tangent fields immediately downstream of the implant. It was also shown that the silicone elastomer shell of the tissue expander reduced the dose to the target volume by as much as 8%. This work demonstrates the importance for an accurately modelled high-density implant in the treatment planning system for post-mastectomy breast cancer patients.

Pharmacokinetics and tissue distribution of psammaplin A, a novel anticancer agent, in mice.

PubMed

Kim, Hak Jae; Kim, Tae Hwan; Seo, Won Sik; Yoo, Sun Dong; Kim, Il Han; Joo, Sang Hoon; Shin, Soyoung; Park, Eun-Seok; Ma, Eun Sook; Shin, Beom Soo

2012-10-01

This study reports the pharmacokinetics and tissue distribution of a novel histone deacetylase and DNA methyltransferase inhibitor, psammaplin A (PsA), in mice. PsA concentrations were determined by a validated LC-MS/MS assay method (LLOQ 2 ng/mL). Following intravenous injection at a dose of 10 mg/kg in mice, PsA was rapidly eliminated, with the average half-life (t(1/2, λn)) of 9.9 ± 1.4 min and the systemic clearance (CL(s)) of 925.1 ± 570.1 mL/min. The in vitro stability of PsA was determined in different tissue homogenates. The average degradation t(1/2) of PsA in blood, liver, kidney and lung was found relatively short (≤ 12.8 min). Concerning the in vivo tissue distribution characteristics, PsA was found to be highly distributed to lung tissues, with the lung-to-serum partition coefficients (K(p)) ranging from 49.9 to 60.2. In contrast, PsA concentrations in other tissues were either comparable with or less than serum concentrations. The high and specific lung targeting characteristics indicates that PsA has the potential to be developed as a lung cancer treatment agent.

The model of drugs distribution dynamics in biological tissue

NASA Astrophysics Data System (ADS)

Ginevskij, D. A.; Izhevskij, P. V.; Sheino, I. N.

2017-09-01

The dose distribution by Neutron Capture Therapy follows the distribution of 10B in the tissue. The modern models of pharmacokinetics of drugs describe the processes occurring in conditioned "chambers" (blood-organ-tumor), but fail to describe the spatial distribution of the drug in the tumor and in normal tissue. The mathematical model of the spatial distribution dynamics of drugs in the tissue, depending on the concentration of the drug in the blood, was developed. The modeling method is the representation of the biological structure in the form of a randomly inhomogeneous medium in which the 10B distribution occurs. The parameters of the model, which cannot be determined rigorously in the experiment, are taken as the quantities subject to the laws of the unconnected random processes. The estimates of 10B distribution preparations in the tumor and healthy tissue, inside/outside the cells, are obtained.

Fluorescent imaging of cancerous tissues for targeted surgery

PubMed Central

Bu, Lihong; Shen, Baozhong; Cheng, Zhen

2014-01-01

To maximize tumor excision and minimize collateral damage is the primary goal of cancer surgery. Emerging molecular imaging techniques have to “image-guided surgery” developing into “molecular imaging-guided surgery”, which is termed “targeted surgery” in this review. Consequently, the precision of surgery can be advanced from tissue-scale to molecule-scale, enabling “targeted surgery” to be a component of “targeted therapy”. Evidence from numerous experimental and clinical studies has demonstrated significant benefits of fluorescent imaging in targeted surgery with preoperative molecular diagnostic screening. Fluorescent imaging can help to improve intraoperative staging and enable more radical cytoreduction, detect obscure tumor lesions in special organs, highlight tumor margins, better map lymph node metastases, and identify important normal structures intraoperatively. Though limited tissue penetration of fluorescent imaging and tumor heterogeneity are two major hurdles for current targeted surgery, multimodality imaging and multiplex imaging may provide potential solutions to overcome these issues, respectively. Moreover, though many fluorescent imaging techniques and probes have been investigated, targeted surgery remains at a proof-of-principle stage. The impact of fluorescent imaging on cancer surgery will likely be realized through persistent interdisciplinary amalgamation of research in diverse fields. PMID:25064553

Overall Adiposity, Adipose Tissue Distribution, and Endometriosis: A Systematic Review.

PubMed

Backonja, Uba; Buck Louis, Germaine M; Lauver, Diane R

2016-01-01

Endometriosis has been associated with a lean body habitus. However, we do not understand whether endometriosis is also associated with other characteristics of adiposity, including adipose tissue distribution and amount of visceral adipose tissue (VAT; adipose tissue lining inner organs). Having these understandings may provide insights on how endometriosis develops-some of the physiological actions of adipose tissue differ depending on tissue amount and location and are related to proposed mechanisms of endometriosis development. The aim of this study was to review the literature regarding overall adiposity, adipose tissue distribution and/or VAT, and endometriosis. We reviewed and synthesized studies indexed in PubMed and/or Web of Science. We included studies that had one or more measures of overall adiposity, adipose tissue distribution, and/or VAT and women with and without endometriosis for comparison. We summarized the findings and commented on the methods used and potential sources of bias. Of 366 identified publications, 19 (5.2%) were eligible. Two additional publications were identified from reference lists. Current research included measures of overall adiposity (e.g., body figure drawings) or adipose tissue distribution (e.g., waist-to-hip ratio), but not VAT. The weight of evidence indicated that endometriosis was associated with low overall adiposity and with a preponderance of adipose tissue distributed below the waist (peripheral). Endometriosis may be associated with being lean or having peripherally distributed adipose tissue. Well-designed studies with various sampling frameworks and precise measures of adiposity and endometriosis are needed to confirm associations between adiposity measures and endometriosis and delineate potential etiological mechanisms underlying endometriosis.

Overall Adiposity, Adipose Tissue Distribution, and Endometriosis: A Systematic Review

PubMed Central

Backonja, Uba; Buck Louis, Germaine M.; Lauver, Diane R.

2015-01-01

Background Endometriosis has been associated with a lean body habitus. However, we do not understand whether endometriosis is also associated with other characteristics of adiposity, including adipose tissue distribution and amount of visceral adipose tissue (VAT; adipose tissue lining inner organs). Having these understandings may provide insights on how endometriosis develops—some of the physiologic actions of adipose tissue differ depending on tissue amount and location, and are related to proposed mechanisms of endometriosis development. Objectives To review the literature regarding overall adiposity, adipose tissue distribution and/or VAT, and endometriosis. Methods We reviewed and synthesized studies indexed in PubMed and/or Web of Science. We included studies that had one or more measures of overall adiposity, adipose tissue distribution, and/or VAT, and women with and without endometriosis for comparison. We summarized the findings and commented on the methods used and potential sources of bias. Results Out of 366 identified publications, 19 (5.2%) were eligible. Two additional publications were identified from reference lists. Current research included measures of overall adiposity (e.g., body figure drawings) or adipose tissue distribution (e.g., waist-to-hip ratio), but not VAT. The weight of evidence indicated that endometriosis was associated with low overall adiposity and with a preponderance of adipose tissue distributed below the waist (peripheral). Discussion Endometriosis may be associated with being lean or having peripherally distributed adipose tissue. Well-designed studies with various sampling frameworks and precise measures of adiposity and endometriosis are needed to confirm associations between adiposity measures and endometriosis, and delineate potential etiologic mechanisms underlying endometriosis. PMID:26938364

Melatonin membrane receptors in peripheral tissues: Distribution and functions

PubMed Central

Slominski, Radomir M.; Reiter, Russel J.; Schlabritz-Loutsevitch, Natalia; Ostrom, Rennolds S.; Slominski, Andrzej T.

2012-01-01

Many of melatonin’s actions are mediated through interaction with the G-protein coupled membrane bound melatonin receptors type 1 and type 2 (MT1 and MT2, respectively) or, indirectly with nuclear orphan receptors from the RORα/RZR family. Melatonin also binds to the quinone reductase II enzyme, previously defined the MT3 receptor. Melatonin receptors are widely distributed in the body; herein we summarize their expression and actions in non-neural tissues. Several controversies still exist regarding, for example, whether melatonin binds the RORα/RZR family. Studies of the peripheral distribution of melatonin receptors are important since they are attractive targets for immunomodulation, regulation of endocrine, reproductive and cardiovascular functions, modulation of skin pigmentation, hair growth, cancerogenesis, and aging. Melatonin receptor agonists and antagonists have an exciting future since they could define multiple mechanisms by which melatonin modulates the complexity of such a wide variety of physiological and pathological processes. PMID:22245784

Sex- and Tissue-specific Functions of Drosophila Doublesex Transcription Factor Target Genes

PubMed Central

Clough, Emily; Jimenez, Erin; Kim, Yoo-Ah; Whitworth, Cale; Neville, Megan C.; Hempel, Leonie; Pavlou, Hania J.; Chen, Zhen-Xia; Sturgill, David; Dale, Ryan; Smith, Harold E.; Przytycka, Teresa M.; Goodwin, Stephen F.; Van Doren, Mark; Oliver, Brian

2014-01-01

Primary sex determination “switches” evolve rapidly, but Doublesex (DSX) related transcription factors (DMRTs) act downstream of these switches to control sexual development in most animal species. Drosophila dsx encodes female- and male-specific isoforms (DSXF and DSXM), but little is known about how dsx controls sexual development, whether DSXF and DSXM bind different targets, or how DSX proteins direct different outcomes in diverse tissues. We undertook genome-wide analyses to identify DSX targets using in vivo occupancy, binding site prediction, and evolutionary conservation. We find that DSXF and DSXM bind thousands of the same targets in multiple tissues in both sexes, yet these targets have sex- and tissue-specific functions. Interestingly, DSX targets show considerable overlap with targets identified for mouse DMRT1. DSX targets include transcription factors and signaling pathway components providing for direct and indirect regulation of sex-biased expression. PMID:25535918

Absorption, distribution and excretion of the anti-tuberculosis drug delamanid in rats: Extensive tissue distribution suggests potential therapeutic value for extrapulmonary tuberculosis.

PubMed

Shibata, Masakazu; Shimokawa, Yoshihiko; Sasahara, Katsunori; Yoda, Noriaki; Sasabe, Hiroyuki; Suzuki, Mitsunari; Umehara, Ken

2017-05-01

Delamanid (OPC-67683, Deltyba™, nitro-dihydro-imidazooxazoles derivative) is approved for the treatment of adult pulmonary multidrug-resistant tuberculosis. The absorption, distribution and excretion of delamanid-derived radioactivity were investigated after a single oral administration of 14 C-delamanid at 3 mg/kg to rats. In both male and female rats, radioactivity in blood and all tissues reached peak levels by 8 or 24 h post-dose, and thereafter decreased slowly. Radioactivity levels were 3- to 5-fold higher in lung tissue at time to maximum concentration compared with plasma. In addition, radioactivity was broadly distributed in various tissues, including the central nervous system, eyeball, placenta and fetus, indicating that 14 C-delamanid permeated the brain, retinal and placental blood barriers. By 168 h post-dose, radioactivity in almost all the tissues was higher than that in the plasma. Radioactivity was also transferred into the milk of lactating rats. Approximately 6% and 92% of radioactivity was excreted in the urine and feces, respectively, indicating that the absorbed radioactivity was primarily excreted via the biliary route. No significant differences in the absorption, distribution and excretion of 14 C-delamanid were observed between male and female rats. The pharmacokinetic results suggested that delamanid was broadly distributed to the lungs and various tissues for a prolonged duration of time at concentrations expected to effectively target tuberculosis bacteria. These data indicate that delamanid, in addition to its previously demonstrated efficacy in pulmonary tuberculosis, might be an effective therapeutic approach to treating extrapulmonary tuberculosis. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

External calibration of polarimetric radars using point and distributed targets

NASA Technical Reports Server (NTRS)

Yueh, S. H.; Kong, J. A.; Shin, R. T.

1991-01-01

Polarimetric calibration algorithms using combinations of point targets and reciprocal distributed targets are developed. From the reciprocity relations of distributed targets, and equivalent point target response is derived. Then the problem of polarimetric calibration using two point targets and one distributed target reduces to that using three point targets, which has been previously solved. For calibration using one point target and one reciprocal distributed target, two cases are analyzed with the point target being a trihedral reflector or a polarimetric active radar calibrator (PARC). For both cases, the general solutions of the system distortion matrices are written as a product of a particular solution and a matrix with one free parameter. For the trihedral-reflector case, this free parameter is determined by assuming azimuthal symmetry for the distributed target. For the PARC case, knowledge of one ratio of two covariance matrix elements of the distributed target is required to solve for the free parameter. Numerical results are simulated to demonstrate the usefulness of the developed algorithms.

External calibration of polarimetric radars using point and distributed targets

NASA Astrophysics Data System (ADS)

Yueh, S. H.; Kong, J. A.; Shin, R. T.

1991-08-01

Polarimetric calibration algorithms using combinations of point targets and reciprocal distributed targets are developed. From the reciprocity relations of distributed targets, and equivalent point target response is derived. Then the problem of polarimetric calibration using two point targets and one distributed target reduces to that using three point targets, which has been previously solved. For calibration using one point target and one reciprocal distributed target, two cases are analyzed with the point target being a trihedral reflector or a polarimetric active radar calibrator (PARC). For both cases, the general solutions of the system distortion matrices are written as a product of a particular solution and a matrix with one free parameter. For the trihedral-reflector case, this free parameter is determined by assuming azimuthal symmetry for the distributed target. For the PARC case, knowledge of one ratio of two covariance matrix elements of the distributed target is required to solve for the free parameter. Numerical results are simulated to demonstrate the usefulness of the developed algorithms.

Method to Reduce Target Motion Through Needle-Tissue Interactions.

PubMed

Oldfield, Matthew J; Leibinger, Alexander; Seah, Tian En Timothy; Rodriguez Y Baena, Ferdinando

2015-11-01

During minimally invasive surgical procedures, it is often important to deliver needles to particular tissue volumes. Needles, when interacting with a substrate, cause deformation and target motion. To reduce reliance on compensatory intra-operative imaging, a needle design and novel delivery mechanism is proposed. Three-dimensional finite element simulations of a multi-segment needle inserted into a pre-existing crack are presented. The motion profiles of the needle segments are varied to identify methods that reduce target motion. Experiments are then performed by inserting a needle into a gelatine tissue phantom and measuring the internal target motion using digital image correlation. Simulations indicate that target motion is reduced when needle segments are stroked cyclically and utilise a small amount of retraction instead of being held stationary. Results are confirmed experimentally by statistically significant target motion reductions of more than 8% during cyclic strokes and 29% when also incorporating retraction, with the same net insertion speed. By using a multi-segment needle and taking advantage of frictional interactions on the needle surface, it is demonstrated that target motion ahead of an advancing needle can be substantially reduced.

Hierarchical Targeting Strategy for Enhanced Tumor Tissue Accumulation/Retention and Cellular Internalization.

PubMed

Wang, Sheng; Huang, Peng; Chen, Xiaoyuan

2016-09-01

Targeted delivery of therapeutic agents is an important way to improve the therapeutic index and reduce side effects. To design nanoparticles for targeted delivery, both enhanced tumor tissue accumulation/retention and enhanced cellular internalization should be considered simultaneously. So far, there have been very few nanoparticles with immutable structures that can achieve this goal efficiently. Hierarchical targeting, a novel targeting strategy based on stimuli responsiveness, shows good potential to enhance both tumor tissue accumulation/retention and cellular internalization. Here, the recent design and development of hierarchical targeting nanoplatforms, based on changeable particle sizes, switchable surface charges and activatable surface ligands, will be introduced. In general, the targeting moieties in these nanoplatforms are not activated during blood circulation for efficient tumor tissue accumulation, but re-activated by certain internal or external stimuli in the tumor microenvironment for enhanced cellular internalization. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Noncontact 3-D Speckle Contrast Diffuse Correlation Tomography of Tissue Blood Flow Distribution.

PubMed

Huang, Chong; Irwin, Daniel; Zhao, Mingjun; Shang, Yu; Agochukwu, Nneamaka; Wong, Lesley; Yu, Guoqiang

2017-10-01

Recent advancements in near-infrared diffuse correlation techniques and instrumentation have opened the path for versatile deep tissue microvasculature blood flow imaging systems. Despite this progress there remains a need for a completely noncontact, noninvasive device with high translatability from small/testing (animal) to large/target (human) subjects with trivial application on both. Accordingly, we discuss our newly developed setup which meets this demand, termed noncontact speckle contrast diffuse correlation tomography (nc_scDCT). The nc_scDCT provides fast, continuous, portable, noninvasive, and inexpensive acquisition of 3-D tomographic deep (up to 10 mm) tissue blood flow distributions with straightforward design and customization. The features presented include a finite-element-method implementation for incorporating complex tissue boundaries, fully noncontact hardware for avoiding tissue compression and interactions, rapid data collection with a diffuse speckle contrast method, reflectance-based design promoting experimental translation, extensibility to related techniques, and robust adjustable source and detector patterns and density for high resolution measurement with flexible regions of interest enabling unique application-specific setups. Validation is shown in the detection and characterization of both high and low contrasts in flow relative to the background using tissue phantoms with a pump-connected tube (high) and phantom spheres (low). Furthermore, in vivo validation of extracting spatiotemporal 3-D blood flow distributions and hyperemic response during forearm cuff occlusion is demonstrated. Finally, the success of instrument feasibility in clinical use is examined through the intraoperative imaging of mastectomy skin flap.

Tissue Distribution Of Chloroaluminium Sulfonated Phthalocyanine In Dogs

NASA Astrophysics Data System (ADS)

M. M.; H. C.; Newman

1989-06-01

Chloroaluminum sulfonated phthalocyanine (A1PCS) was administered intravenously to clinically normal dogs, and A1PCS levels were determined in tissues using a sensitive assay. A1PCS accumulated to high levels in liver, spleen, bone marrow, kidney, and lung. These tissue levels confirm previous determinations in mice and rats. Only a small amount of dye was retained in skin and very small amounts in muscle and brain. A1PCS was cleared from the blood within 24 h, and excreted primarily by urine. Serum clearance was faster in males than in females. There were also significant tissue distribution differences between the genders, particularly during the first 12 h. The low levels of A1PCS in skin suggest that cutaneous photosensitivity and toxic skin reactions using this photosensitizer in photodynamic therapy of cancer may be eliminated. The difference in tissue distribution between genders is not only intriguing, but indicates that the optimal time window for treatment of various tissue sites may vary by gender.

An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2

PubMed Central

Boswell, C Andrew; Mundo, Eduardo E; Firestein, Ron; Zhang, Crystal; Mao, Weiguang; Gill, Herman; Young, Cynthia; Ljumanovic, Nina; Stainton, Shannon; Ulufatu, Sheila; Fourie, Aimee; Kozak, Katherine R; Fuji, Reina; Polakis, Paul; Khawli, Leslie A; Lin, Kedan

2013-01-01

Background and Purpose The success of antibody-drug conjugates (ADCs) depends on the therapeutic window rendered by the differential expression between normal and pathological tissues. The ability to identify and visualize target expression in normal tissues could reveal causes for target-mediated clearance observed in pharmacokinetic characterization. TENB2 is a prostate cancer target associated with the progression of poorly differentiated and androgen-independent tumour types, and ADCs specific for TENB2 are candidate therapeutics. The objective of this study was to locate antigen expression of TENB2 in normal tissues, thereby elucidating the underlying causes of target-mediated clearance. Experimental Approach A series of pharmacokinetics, tissue distribution and mass balance studies were conducted in mice using a radiolabelled anti-TENB2 ADC. These data were complemented by non-invasive single photon emission computed tomography – X-ray computed tomography imaging and immunohistochemistry. Key Results The intestines were identified as a saturable and specific antigen sink that contributes, at least in part, to the rapid target-mediated clearance of the anti-TENB2 antibody and its drug conjugate in rodents. As a proof of concept, we also demonstrated the selective disposition of the ADC in a tumoural environment in vivo using the LuCaP 77 transplant mouse model. High tumour uptake was observed despite the presence of the antigen sink, and antigen specificity was confirmed by antigen blockade. Conclusions and Implications Our findings provide the anatomical location and biological interpretation of target-mediated clearance of anti-TENB2 antibodies and corresponding drug conjugates. Further investigations may be beneficial in addressing the relative contributions to ADC disposition from antigen expression in both normal and pathological tissues. PMID:22889168

An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2.

PubMed

Boswell, C Andrew; Mundo, Eduardo E; Firestein, Ron; Zhang, Crystal; Mao, Weiguang; Gill, Herman; Young, Cynthia; Ljumanovic, Nina; Stainton, Shannon; Ulufatu, Sheila; Fourie, Aimee; Kozak, Katherine R; Fuji, Reina; Polakis, Paul; Khawli, Leslie A; Lin, Kedan

2013-01-01

The success of antibody-drug conjugates (ADCs) depends on the therapeutic window rendered by the differential expression between normal and pathological tissues. The ability to identify and visualize target expression in normal tissues could reveal causes for target-mediated clearance observed in pharmacokinetic characterization. TENB2 is a prostate cancer target associated with the progression of poorly differentiated and androgen-independent tumour types, and ADCs specific for TENB2 are candidate therapeutics. The objective of this study was to locate antigen expression of TENB2 in normal tissues, thereby elucidating the underlying causes of target-mediated clearance. A series of pharmacokinetics, tissue distribution and mass balance studies were conducted in mice using a radiolabelled anti-TENB2 ADC. These data were complemented by non-invasive single photon emission computed tomography - X-ray computed tomography imaging and immunohistochemistry. The intestines were identified as a saturable and specific antigen sink that contributes, at least in part, to the rapid target-mediated clearance of the anti-TENB2 antibody and its drug conjugate in rodents. As a proof of concept, we also demonstrated the selective disposition of the ADC in a tumoural environment in vivo using the LuCaP 77 transplant mouse model. High tumour uptake was observed despite the presence of the antigen sink, and antigen specificity was confirmed by antigen blockade. Our findings provide the anatomical location and biological interpretation of target-mediated clearance of anti-TENB2 antibodies and corresponding drug conjugates. Further investigations may be beneficial in addressing the relative contributions to ADC disposition from antigen expression in both normal and pathological tissues. © 2012 Genentech, Inc.. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Effects of Phytochemical P-Glycoprotein Modulators on the Pharmacokinetics and Tissue Distribution of Doxorubicin in Mice.

PubMed

Kim, Tae Hwan; Shin, Soyoung; Yoo, Sun Dong; Shin, Beom Soo

2018-02-07

Pungent spice constituents such as piperine, capsaicin and [6]-gingerol consumed via daily diet or traditional Chinese medicine, have been reported to possess various pharmacological activities. These dietary phytochemicals have also been reported to inhibit P-glycoprotein (P-gp) in vitro and act as an alternative to synthetic P-gp modulators. However, the in vivo effects on P-gp inhibition are currently unknown. This study aimed to test the hypothesis that phytochemical P-gp inhibitors, i.e., piperine, capsaicin and [6]-gingerol, modulate the in vivo tissue distribution of doxorubicin, a representative P-gp substrate. Mice were divided into four groups and each group was pretreated with intraperitoneal injections of control vehicle, piperine, capsaicin, or [6]-gingerol and doxorubicin (1 mg/kg) was administered via the penile vein. The concentrations of the phytochemicals and doxorubicin in the plasma and tissues were determined by LC-MS/MS. The overall plasma concentration-time profiles of doxorubicin were not significantly affected by piperine, capsaicin, or [6]-gingerol. In contrast, doxorubicin accumulation was observed in tissues pretreated with piperine or capsaicin. The tissue to plasma partition coefficients, K p , for the liver and kidney were higher in the piperine-pretreated group, while the K p for kidney, brain and liver were higher in the capsaicin-pretreated group. [6]-Gingerol did not affect doxorubicin tissue distribution. The data demonstrated that the phytochemicals modulated doxorubicin tissue distribution, which suggested their potential to induce food-drug interactions and act as a strategy for the delivery of P-gp substrate drugs to target tissues and tumors.

Distribution of PLGA-modified nanoparticles in 3D cell culture models of hypo-vascularized tumor tissue.

PubMed

Sims, Lee B; Huss, Maya K; Frieboes, Hermann B; Steinbach-Rankins, Jill M

2017-10-05

Advanced stage cancer treatments are often invasive and painful-typically comprised of surgery, chemotherapy, and/or radiation treatment. Low transport efficiency during systemic chemotherapy may require high chemotherapeutic doses to effectively target cancerous tissue, resulting in systemic toxicity. Nanotherapeutic platforms have been proposed as an alternative to more safely and effectively deliver therapeutic agents directly to tumor sites. However, cellular internalization and tumor penetration are often diametrically opposed, with limited access to tumor regions distal from vasculature, due to irregular tissue morphologies. To address these transport challenges, nanoparticles (NPs) are often surface-modified with ligands to enhance transport and longevity after localized or systemic administration. Here, we evaluate stealth polyethylene-glycol (PEG), cell-penetrating (MPG), and CPP-stealth (MPG/PEG) poly(lactic-co-glycolic-acid) (PLGA) NP co-treatment strategies in 3D cell culture representing hypo-vascularized tissue. Smaller, more regularly-shaped avascular tissue was generated using the hanging drop (HD) method, while more irregularly-shaped masses were formed with the liquid overlay (LO) technique. To compare NP distribution differences within the same type of tissue as a function of different cancer types, we selected HeLa, cervical epithelial adenocarcinoma cells; CaSki, cervical epidermoid carcinoma cells; and SiHa, grade II cervical squamous cell carcinoma cells. In HD tumors, enhanced distribution relative to unmodified NPs was measured for MPG and PEG NPs in HeLa, and for all modified NPs in SiHa spheroids. In LO tumors, the greatest distribution was observed for MPG and MPG/PEG NPs in HeLa, and for PEG and MPG/PEG NPs in SiHa spheroids. Pre-clinical evaluation of PLGA-modified NP distribution into hypo-vascularized tumor tissue may benefit from considering tissue morphology in addition to cancer type.

Cell-size distribution in epithelial tissue formation and homeostasis

PubMed Central

Primo, Luca; Celani, Antonio

2017-01-01

How cell growth and proliferation are orchestrated in living tissues to achieve a given biological function is a central problem in biology. During development, tissue regeneration and homeostasis, cell proliferation must be coordinated by spatial cues in order for cells to attain the correct size and shape. Biological tissues also feature a notable homogeneity of cell size, which, in specific cases, represents a physiological need. Here, we study the temporal evolution of the cell-size distribution by applying the theory of kinetic fragmentation to tissue development and homeostasis. Our theory predicts self-similar probability density function (PDF) of cell size and explains how division times and redistribution ensure cell size homogeneity across the tissue. Theoretical predictions and numerical simulations of confluent non-homeostatic tissue cultures show that cell size distribution is self-similar. Our experimental data confirm predictions and reveal that, as assumed in the theory, cell division times scale like a power-law of the cell size. We find that in homeostatic conditions there is a stationary distribution with lognormal tails, consistently with our experimental data. Our theoretical predictions and numerical simulations show that the shape of the PDF depends on how the space inherited by apoptotic cells is redistributed and that apoptotic cell rates might also depend on size. PMID:28330988

Stationary Temperature Distribution in a Rotating Ring-Shaped Target

NASA Astrophysics Data System (ADS)

Kazarinov, N. Yu.; Gulbekyan, G. G.; Kazacha, V. I.

2018-05-01

For a rotating ring-shaped target irradiated by a heavy-ion beam, a differential equation for computing the stationary distribution of the temperature averaged over the cross section is derived. The ion-beam diameter is assumed to be equal to the ring width. Solving this equation allows one to obtain the stationary temperature distribution along the ring-shaped target depending on the ion-beam, target, and cooling-gas parameters. Predictions are obtained for the rotating target to be installed at the DC-280 cyclotron. For an existing rotating target irradiated by an ion beam, our predictions are compared with the measured temperature distribution.

Cell-size distribution in epithelial tissue formation and homeostasis.

PubMed

Puliafito, Alberto; Primo, Luca; Celani, Antonio

2017-03-01

How cell growth and proliferation are orchestrated in living tissues to achieve a given biological function is a central problem in biology. During development, tissue regeneration and homeostasis, cell proliferation must be coordinated by spatial cues in order for cells to attain the correct size and shape. Biological tissues also feature a notable homogeneity of cell size, which, in specific cases, represents a physiological need. Here, we study the temporal evolution of the cell-size distribution by applying the theory of kinetic fragmentation to tissue development and homeostasis. Our theory predicts self-similar probability density function (PDF) of cell size and explains how division times and redistribution ensure cell size homogeneity across the tissue. Theoretical predictions and numerical simulations of confluent non-homeostatic tissue cultures show that cell size distribution is self-similar. Our experimental data confirm predictions and reveal that, as assumed in the theory, cell division times scale like a power-law of the cell size. We find that in homeostatic conditions there is a stationary distribution with lognormal tails, consistently with our experimental data. Our theoretical predictions and numerical simulations show that the shape of the PDF depends on how the space inherited by apoptotic cells is redistributed and that apoptotic cell rates might also depend on size. © 2017 The Author(s).

Magnetoferritin nanoparticles for targeting and visualizing tumour tissues

NASA Astrophysics Data System (ADS)

Fan, Kelong; Cao, Changqian; Pan, Yongxin; Lu, Di; Yang, Dongling; Feng, Jing; Song, Lina; Liang, Minmin; Yan, Xiyun

2012-07-01

Engineered nanoparticles have been used to provide diagnostic, therapeutic and prognostic information about the status of disease. Nanoparticles developed for these purposes are typically modified with targeting ligands (such as antibodies, peptides or small molecules) or contrast agents using complicated processes and expensive reagents. Moreover, this approach can lead to an excess of ligands on the nanoparticle surface, and this causes non-specific binding and aggregation of nanoparticles, which decreases detection sensitivity. Here, we show that magnetoferritin nanoparticles (M-HFn) can be used to target and visualize tumour tissues without the use of any targeting ligands or contrast agents. Iron oxide nanoparticles are encapsulated inside a recombinant human heavy-chain ferritin (HFn) protein shell, which binds to tumour cells that overexpress transferrin receptor 1 (TfR1). The iron oxide core catalyses the oxidation of peroxidase substrates in the presence of hydrogen peroxide to produce a colour reaction that is used to visualize tumour tissues. We examined 474 clinical specimens from patients with nine types of cancer and verified that these nanoparticles can distinguish cancerous cells from normal cells with a sensitivity of 98% and specificity of 95%.

PREDICTING THE RISKS OF NEUROTOXIC VOLATILE ORGANIC COMPOUNDS BASED ON TARGET TISSUE DOSE.

EPA Science Inventory

Quantitative exposure-dose-response models relate the external exposure of a substance to the dose in the target tissue, and then relate the target tissue dose to production of adverse outcomes. We developed exposure-dose-response models to describe the affects of acute exposure...

Pilots' Attention Distributions Between Chasing a Moving Target and a Stationary Target.

PubMed

Li, Wen-Chin; Yu, Chung-San; Braithwaite, Graham; Greaves, Matthew

2016-12-01

Attention plays a central role in cognitive processing; ineffective attention may induce accidents in flight operations. The objective of the current research was to examine military pilots' attention distributions between chasing a moving target and a stationary target. In the current research, 37 mission-ready F-16 pilots participated. Subjects' eye movements were collected by a portable head-mounted eye-tracker during tactical training in a flight simulator. The scenarios of chasing a moving target (air-to-air) and a stationary target (air-to-surface) consist of three operational phases: searching, aiming, and lock-on to the targets. The findings demonstrated significant differences in pilots' percentage of fixation during the searching phase between air-to-air (M = 37.57, SD = 5.72) and air-to-surface (M = 33.54, SD = 4.68). Fixation duration can indicate pilots' sustained attention to the trajectory of a dynamic target during air combat maneuvers. Aiming at the stationary target resulted in larger pupil size (M = 27,105, SD = 6565), reflecting higher cognitive loading than aiming at the dynamic target (M = 23,864, SD = 8762). Pilots' visual behavior is not only closely related to attention distribution, but also significantly associated with task characteristics. Military pilots demonstrated various visual scan patterns for searching and aiming at different types of targets based on the research settings of a flight simulator. The findings will facilitate system designers' understanding of military pilots' cognitive processes during tactical operations. They will assist human-centered interface design to improve pilots' situational awareness. The application of an eye-tracking device integrated with a flight simulator is a feasible and cost-effective intervention to improve the efficiency and safety of tactical training.Li W-C, Yu C-S, Braithwaite G, Greaves M. Pilots' attention distributions between chasing a moving target and a stationary target. Aerosp Med

Calculation of dose distribution in compressible breast tissues using finite element modeling, Monte Carlo simulation and thermoluminescence dosimeters

NASA Astrophysics Data System (ADS)

Mohammadyari, Parvin; Faghihi, Reza; Mosleh-Shirazi, Mohammad Amin; Lotfi, Mehrzad; Rahim Hematiyan, Mohammad; Koontz, Craig; Meigooni, Ali S.

2015-12-01

Compression is a technique to immobilize the target or improve the dose distribution within the treatment volume during different irradiation techniques such as AccuBoost® brachytherapy. However, there is no systematic method for determination of dose distribution for uncompressed tissue after irradiation under compression. In this study, the mechanical behavior of breast tissue between compressed and uncompressed states was investigated. With that, a novel method was developed to determine the dose distribution in uncompressed tissue after irradiation of compressed breast tissue. Dosimetry was performed using two different methods, namely, Monte Carlo simulations using the MCNP5 code and measurements using thermoluminescent dosimeters (TLD). The displacement of the breast elements was simulated using a finite element model and calculated using ABAQUS software. From these results, the 3D dose distribution in uncompressed tissue was determined. The geometry of the model was constructed from magnetic resonance images of six different women volunteers. The mechanical properties were modeled by using the Mooney-Rivlin hyperelastic material model. Experimental dosimetry was performed by placing the TLD chips into the polyvinyl alcohol breast equivalent phantom. The results determined that the nodal displacements, due to the gravitational force and the 60 Newton compression forces (with 43% contraction in the loading direction and 37% expansion in the orthogonal direction) were determined. Finally, a comparison of the experimental data and the simulated data showed agreement within 11.5%  ±  5.9%.

Calculation of dose distribution in compressible breast tissues using finite element modeling, Monte Carlo simulation and thermoluminescence dosimeters.

PubMed

Mohammadyari, Parvin; Faghihi, Reza; Mosleh-Shirazi, Mohammad Amin; Lotfi, Mehrzad; Hematiyan, Mohammad Rahim; Koontz, Craig; Meigooni, Ali S

2015-12-07

Compression is a technique to immobilize the target or improve the dose distribution within the treatment volume during different irradiation techniques such as AccuBoost(®) brachytherapy. However, there is no systematic method for determination of dose distribution for uncompressed tissue after irradiation under compression. In this study, the mechanical behavior of breast tissue between compressed and uncompressed states was investigated. With that, a novel method was developed to determine the dose distribution in uncompressed tissue after irradiation of compressed breast tissue. Dosimetry was performed using two different methods, namely, Monte Carlo simulations using the MCNP5 code and measurements using thermoluminescent dosimeters (TLD). The displacement of the breast elements was simulated using a finite element model and calculated using ABAQUS software. From these results, the 3D dose distribution in uncompressed tissue was determined. The geometry of the model was constructed from magnetic resonance images of six different women volunteers. The mechanical properties were modeled by using the Mooney-Rivlin hyperelastic material model. Experimental dosimetry was performed by placing the TLD chips into the polyvinyl alcohol breast equivalent phantom. The results determined that the nodal displacements, due to the gravitational force and the 60 Newton compression forces (with 43% contraction in the loading direction and 37% expansion in the orthogonal direction) were determined. Finally, a comparison of the experimental data and the simulated data showed agreement within 11.5%  ±  5.9%.

Alternative Polyadenylation Directs Tissue-Specific miRNA Targeting in Caenorhabditis elegans Somatic Tissues

PubMed Central

Blazie, Stephen M.; Geissel, Heather C.; Wilky, Henry; Joshi, Rajan; Newbern, Jason; Mangone, Marco

2017-01-01

mRNA expression dynamics promote and maintain the identity of somatic tissues in living organisms; however, their impact in post-transcriptional gene regulation in these processes is not fully understood. Here, we applied the PAT-Seq approach to systematically isolate, sequence, and map tissue-specific mRNA from five highly studied Caenorhabditis elegans somatic tissues: GABAergic and NMDA neurons, arcade and intestinal valve cells, seam cells, and hypodermal tissues, and studied their mRNA expression dynamics. The integration of these datasets with previously profiled transcriptomes of intestine, pharynx, and body muscle tissues, precisely assigns tissue-specific expression dynamics for 60% of all annotated C. elegans protein-coding genes, providing an important resource for the scientific community. The mapping of 15,956 unique high-quality tissue-specific polyA sites in all eight somatic tissues reveals extensive tissue-specific 3′untranslated region (3′UTR) isoform switching through alternative polyadenylation (APA) . Almost all ubiquitously transcribed genes use APA and harbor miRNA targets in their 3′UTRs, which are commonly lost in a tissue-specific manner, suggesting widespread usage of post-transcriptional gene regulation modulated through APA to fine tune tissue-specific protein expression. Within this pool, the human disease gene C. elegans orthologs rack-1 and tct-1 use APA to switch to shorter 3′UTR isoforms in order to evade miRNA regulation in the body muscle tissue, resulting in increased protein expression needed for proper body muscle function. Our results highlight a major positive regulatory role for APA, allowing genes to counteract miRNA regulation on a tissue-specific basis. PMID:28348061

Alternative Polyadenylation Directs Tissue-Specific miRNA Targeting in Caenorhabditis elegans Somatic Tissues.

PubMed

Blazie, Stephen M; Geissel, Heather C; Wilky, Henry; Joshi, Rajan; Newbern, Jason; Mangone, Marco

2017-06-01

mRNA expression dynamics promote and maintain the identity of somatic tissues in living organisms; however, their impact in post-transcriptional gene regulation in these processes is not fully understood. Here, we applied the PAT-Seq approach to systematically isolate, sequence, and map tissue-specific mRNA from five highly studied Caenorhabditis elegans somatic tissues: GABAergic and NMDA neurons, arcade and intestinal valve cells, seam cells, and hypodermal tissues, and studied their mRNA expression dynamics. The integration of these datasets with previously profiled transcriptomes of intestine, pharynx, and body muscle tissues, precisely assigns tissue-specific expression dynamics for 60% of all annotated C. elegans protein-coding genes, providing an important resource for the scientific community. The mapping of 15,956 unique high-quality tissue-specific polyA sites in all eight somatic tissues reveals extensive tissue-specific 3'untranslated region (3'UTR) isoform switching through alternative polyadenylation (APA) . Almost all ubiquitously transcribed genes use APA and harbor miRNA targets in their 3'UTRs, which are commonly lost in a tissue-specific manner, suggesting widespread usage of post-transcriptional gene regulation modulated through APA to fine tune tissue-specific protein expression. Within this pool, the human disease gene C. elegans orthologs rack-1 and tct-1 use APA to switch to shorter 3'UTR isoforms in order to evade miRNA regulation in the body muscle tissue, resulting in increased protein expression needed for proper body muscle function. Our results highlight a major positive regulatory role for APA, allowing genes to counteract miRNA regulation on a tissue-specific basis. Copyright © 2017 Blazie et al.

[Project to enhance bone bank tissue storage and distribution procedures].

PubMed

Huang, Jui-Chen; Wu, Chiung-Lan; Chen, Chun-Chuan; Chen, Shu-Hua

2011-10-01

Organ and tissue transplantation are now commonly preformed procedures. Improper organ bank handling procedures may increase infection risks. Execution accuracy in terms of tissue storage and distribution at our bone bank was 80%. We thus proposed an execution improvement project to enhance procedures in order to fulfill the intent of donors and ensure recipient safety. This project was designed to raise nurse professionalism, and ensure patient safety through enhanced tissue storage and distribution procedures. Education programs developed for this project focus on teaching standard operating procedures for bone and ligament storage and distribution, bone bank facility maintenance, trouble shooting and solutions, and periodic inspection systems. Cognition of proper storage and distribution procedures rose from 81% to 100%; Execution accuracy also rose from 80% to 100%. The project successfully conveyed concepts essential to the correct execution of organ storage and distribution procedures and proper organ bank facility management. Achieving and maintaining procedural and management standards is crucial to continued organ donations and the recipient safety.

Synthetic microRNA cassette dosing: pharmacokinetics, tissue distribution and bioactivity.

PubMed

Wang, Hongyan; Chiu, Ming; Xie, Zhiliang; Chiu, Michael; Liu, Zhongfa; Chen, Ping; Liu, Shujun; Byrd, John C; Muthusamy, Natarajan; Garzon, Ramiro; Croce, Carlo M; Marcucci, Guido; Chan, Kenneth K

2012-06-04

MicroRNAs (miRs) are deregulated in cancer and leukemia. Restoring aberrantly downregulated tumor suppressor miRs or antagonizing overexpressed oncogenic miRs in malignant cells by synthetic RNA oligonucleotides represents a potentially novel therapeutic approach in cancer and leukemia. However, given the complex networking and concurrent deregulation of miRs in malignant cells, an effective approach may require concurrent targeting of multiple miRs. Cassette dosing involves simultaneous administration of a mixture of oligonucleotides from the same or different structural classes. However, information on cassette dosing pharmacokinetics, tissue distribution and bioactivity of synthetic miRs is lacking. In this study, three synthetic 2'-methoxyphosphorothioate-miRs (2'-MeOPSmiR16-1, 2'-MeOPSmiR29b and 2'-MeOPSantagomiR155) were administered iv to C57BL/6 mice as a mixture, each at 7.5 mg/kg. Analysis of concentrations of individual miR in plasma and major organ tissues (bone marrow, spleen, liver, brain, heart, kidney and lung) was performed. The mRNA and protein levels of miR's biotargets were monitored sequentially after dosing up to 24 h. Our results demonstrated that these synthetic miRs retain their different individual pharmacokinetic properties and all display three-compartmental pharmacokinetics. 2'-MeOPSmiR16-1 has the longest plasma gamma half-life of 2508 min and lowest total body clearance of 0.0054 L/min·kg, whereas 2'-MeOPSmiR29b has the shortest gamma half-life of 510.6 min and highest total body clearance of 0.042 L/min·kg. The tissue concentrations of all three 2'-MeOPS-modified miR(s)/antagomiR were measurable from 5 min to at least 24 h after dosing, indicating that these concurrently delivered oligonucleotides can reach organ tissues. Importantly, there were biological activities of the concurrently administered miRs which persisted, as shown by the downregulation of specific targets in tested tissues, albeit with variations. Brain was one of

GENE EXPRESSION PROFILING OF ACCESSIBLE SURROGATE TISSUES TO MONITOR MOLECULAR CHANGES IN INACCESSIBLE TARGET TISSUES FOLLOWING TOXICANT EXPOSURE

EPA Science Inventory

Gene Expression Profiling Of Accessible Surrogate Tissues To Monitor Molecular Changes In Inaccessible Target Tissues Following Toxicant Exposure
John C. Rockett, Chad R. Blystone, Amber K. Goetz, Rachel N. Murrell, Judith E. Schmid and David J. Dix
Reproductive Toxicology ...

Applying the log-normal distribution to target detection

NASA Astrophysics Data System (ADS)

Holst, Gerald C.

1992-09-01

Holst and Pickard experimentally determined that MRT responses tend to follow a log-normal distribution. The log normal distribution appeared reasonable because nearly all visual psychological data is plotted on a logarithmic scale. It has the additional advantage that it is bounded to positive values; an important consideration since probability of detection is often plotted in linear coordinates. Review of published data suggests that the log-normal distribution may have universal applicability. Specifically, the log-normal distribution obtained from MRT tests appears to fit the target transfer function and the probability of detection of rectangular targets.

Expression and distribution of endocan in human tissues.

PubMed

Zhang, S M; Zuo, L; Zhou, Q; Gui, S Y; Shi, R; Wu, Q; Wei, W; Wang, Y

2012-04-01

Endocan is a novel human endothelial cell specific molecule. Its expression is regulated by cytokines and vascular endothelial growth factor (VEGF). The distribution of endocan in normal human tissues, however, remains unclear. We examined the expression of endocan in normal human tissue using immunohistochemical stains. Endocan was expressed in actively proliferative or neogeneic tissues and cells such as glandular tissues, endothelium of neovasculature, bronchial epithelium, germinal centers of lymph nodes etc. Endocan was not present in silent or resting tissues or cells such as endothelium of great arteries and spleen etc. Our findings suggest that endocan may act as a marker for angiogenesis or oncogenesis and could be regarded as a candidate gene for inflammatory tissue, neoplasia, tumor development and metastasis. The expression level of endocan may assist early diagnosis and prognosis of some tumors.

Tissue distribution and elimination after oral and intravenous administration of different titanium dioxide nanoparticles in rats

PubMed Central

2014-01-01

Objective The aim of this study was to obtain kinetic data that can be used in human risk assessment of titanium dioxide nanomaterials. Methods Tissue distribution and blood kinetics of various titanium dioxide nanoparticles (NM-100, NM-101, NM-102, NM-103, and NM-104), which differ with respect to primary particle size, crystalline form and hydrophobicity, were investigated in rats up to 90 days post-exposure after oral and intravenous administration of a single or five repeated doses. Results For the oral study, liver, spleen and mesenteric lymph nodes were selected as target tissues for titanium (Ti) analysis. Ti-levels in liver and spleen were above the detection limit only in some rats. Titanium could be detected at low levels in mesenteric lymph nodes. These results indicate that some minor absorption occurs in the gastrointestinal tract, but to a very limited extent. Both after single and repeated intravenous (IV) exposure, titanium rapidly distributed from the systemic circulation to all tissues evaluated (i.e. liver, spleen, kidney, lung, heart, brain, thymus, reproductive organs). Liver was identified as the main target tissue, followed by spleen and lung. Total recovery (expressed as % of nominal dose) for all four tested nanomaterials measured 24 h after single or repeated exposure ranged from 64-95% or 59-108% for male or female animals, respectively. During the 90 days post-exposure period, some decrease in Ti-levels was observed (mainly for NM-100 and NM-102) with a maximum relative decrease of 26%. This was also confirmed by the results of the kinetic analysis which revealed that for each of the investigated tissues the half-lifes were considerable (range 28–650 days, depending on the TiO2-particle and tissue investigated). Minor differences in kinetic profile were observed between the various particles, though these could not be clearly related to differences in primary particle size or hydrophobicity. Some indications were observed for an

Adipose tissue content and distribution in children and adolescents with bronchial asthma.

PubMed

Umławska, Wioleta

2015-02-01

The excess of adipose tissue and the pattern of adipose tissue distribution in the body seem to play an important role in the complicated dependencies between obesity and risk of developing asthma. The aim of the present study was to determine nutritional status in children and adolescents with bronchial asthma with special emphasis on adipose tissue distribution evaluated on the basis of skin-fold thicknesses, and to determine the relationships between patterns of adipose tissue distribution and the course of the disease. Anthropometric data on height, weight, circumferences and skin-fold thicknesses were extracted from the medical histories of 261 children diagnosed with asthma bronchitis. Values for children with asthma were compared to Polish national growth reference charts. Distribution of subcutaneous adipose tissue was evaluated using principal components analysis (PCA). Multivariate linear regression analyses tested the effect of three factors on subcutaneous adipose tissue distribution: type of asthma, the severity of the disease and the duration of the disease. Mean body height in the children examined in this study was lower than in their healthy peers. Mean BMI and skin-fold thicknesses were significantly higher and lean body mass was lower in the study group. Excess body fat was noted, especially in girls. Adipose tissue was preferentially deposited in the trunk in girls with severe asthma, as well as in those who had been suffering from asthma for a longer time. The type of asthma, atopic or non-atopic, had no observable effect on subcutaneous adipose tissue distribution in children examined. The data suggest that long-treated subjects and those with severe bronchial asthma accumulate more adipose tissue on the trunk. It is important to regularly monitor nutritional status in children with asthma, especially in those receiving high doses of systemic or inhaled glucocorticosteroids, and long-term treatment as well. Copyright © 2014 Elsevier Ltd. All

Characterization, pharmacokinetics and tissue distribution of chlorogenic acid-loaded self-microemulsifying drug delivery system.

PubMed

Chen, Li; Liu, Chang-Shun; Chen, Qing-Zhen; Wang, Sen; Xiong, Yong-Ai; Jing, Jing; Lv, Jia-Jia

2017-03-30

The purpose of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) to improve the oral bioavailability of Chlorogenic acid (CA), an important bioactive compound from Lonicerae Japonicae Flos with poor permeability. SMEDDS was prepared and characterized by self-emulsifying rate, morphological observation, droplet size determination, stability, in vitro release, in vivo bioavailability and tissue distribution experiments. Results shown that the SMEDDS of CA has a high self-emulsifying rate (>98%) in the dissolution media, and its microemulsion exhibits small droplet size (16.37nm) and good stability. In vitro release test showed a complete release of CA from SMEDDS in 480min. After oral administration in mice, significantly enhanced bioavailability of CA was achieved through SMEDDS (249.4% relative to the CA suspension). Interestingly, SMEDDS significantly changed the tissue distribution of CA and showed a better targeting property to the kidney (2.79 of the relative intake efficiency). It is suggested that SMEDDS improves the oral bioavailability of CA may mainly through increasing its absorption and slowing the metabolism of absorbed CA via changing its distribution from the liver to the kidney. In conclusion, it is indicated that SMEDDS is a promising carrier for the oral delivery of CA. Copyright © 2017 Elsevier B.V. All rights reserved.

Drosophila CLOCK target gene characterization: implications for circadian tissue-specific gene expression

PubMed Central

Abruzzi, Katharine Compton; Rodriguez, Joseph; Menet, Jerome S.; Desrochers, Jennifer; Zadina, Abigail; Luo, Weifei; Tkachev, Sasha; Rosbash, Michael

2011-01-01

CLOCK (CLK) is a master transcriptional regulator of the circadian clock in Drosophila. To identify CLK direct target genes and address circadian transcriptional regulation in Drosophila, we performed chromatin immunoprecipitation (ChIP) tiling array assays (ChIP–chip) with a number of circadian proteins. CLK binding cycles on at least 800 sites with maximal binding in the early night. The CLK partner protein CYCLE (CYC) is on most of these sites. The CLK/CYC heterodimer is joined 4–6 h later by the transcriptional repressor PERIOD (PER), indicating that the majority of CLK targets are regulated similarly to core circadian genes. About 30% of target genes also show cycling RNA polymerase II (Pol II) binding. Many of these generate cycling RNAs despite not being documented in prior RNA cycling studies. This is due in part to different RNA isoforms and to fly head tissue heterogeneity. CLK has specific targets in different tissues, implying that important CLK partner proteins and/or mechanisms contribute to gene-specific and tissue-specific regulation. PMID:22085964

Histone-Targeted Nucleic Acid Delivery for Tissue Regenerative Applications

NASA Astrophysics Data System (ADS)

Munsell, Erik V.

Nucleic acid delivery has garnered significant attention as an innovative therapeutic approach for treating a wide variety of diseases. However, the design of non-viral delivery systems that negotiate efficient intracellular trafficking and nuclear entry represents a significant challenge. Overcoming these hurdles requires a combination of well-controlled materials approaches with techniques to understand and direct cellular delivery. Recent investigations have highlighted the roles histone tail sequences play in directing nuclear delivery and retention, as well as activating DNA transcription. We established the ability to recapitulate these natural histone tail activities within non-viral gene nanocarriers, driving gene transfer/expression by enabling effective navigation to the nucleus via retrograde vesicular trafficking. A unique finding of this histone-targeted approach was that nanocarriers gained enhanced access to the nucleus during mitosis. The work described in this dissertation builds off of these fundamental insights to facilitate the translation of this histone-targeted delivery approach toward regenerative medicine applications. During native tissue repair, actively proliferating mesenchymal stem cells (MSCs) respond to a complex series of growth factor signals that direct their differentiation. Accordingly, the investigations in this work focused on utilizing the histone-targeted nanocarriers to enhance osteogenic growth factor gene transfer in dividing MSCs leading to augmented MSC chondrogenic differentiation, an essential first step in skeletal tissue repair. Concurrently, additional studies focused on optimizing the histone-targeted nanocarrier design strategy to enable improved plasmid DNA (pDNA) binding stability and tunable harnessing of native cellular processing pathways for enhanced gene transfer. Overall, the work presented herein demonstrated substantial increases in growth factor expression following histone-targeted gene transfer. This

Localized increase of tissue oxygen tension by magnetic targeted drug delivery

NASA Astrophysics Data System (ADS)

Liong, Celine; Ortiz, Daniel; Ao-ieong, Eilleen; Navati, Mahantesh S.; Friedman, Joel M.; Cabrales, Pedro

2014-07-01

Hypoxia is the major hindrance to successful radiation therapy of tumors. Attempts to increase the oxygen (O2) tension (PO2) of tissue by delivering more O2 have been clinically disappointing, largely due to the way O2 is transported and released by the hemoglobin (Hb) within the red blood cells (RBCs). Systemic manipulation of O2 transport increases vascular resistance due to metabolic autoregulation of blood flow to prevent over oxygenation. This study investigates a new technology to increase O2 delivery to a target tissue by decreasing the Hb-O2 affinity of the blood circulating within the targeted tissue. As the Hb-O2 affinity decreases, the tissue PO2 to satisfy tissue O2 metabolic needs increases without increasing O2 delivery or extraction. Paramagnetic nanoparticles (PMNPs), synthetized using gadolinium oxide, were coated with the cell permeable Hb allosteric effector L35 (3,5-trichlorophenylureido-phenoxy-methylpropionic acid). L35 decreases Hb affinity for O2 and favors the release of O2. The L35-coated PMNPs (L35-PMNPs) were intravenously infused (10 mg kg-1) to hamsters instrumented with the dorsal window chamber model. A magnetic field of 3 mT was applied to localize the effects of the L35-PMNPs to the window chamber. Systemic O2 transport characteristics and microvascular tissue oxygenation were measured after administration of L35-PMNPs with and without magnetic field. The tissue PO2 in untreated control animals was 25.2 mmHg. L35-PMNPs without magnetic field decreased tissue PO2 to 23.4 mmHg, increased blood pressure, and reduced blood flow, largely due to systemic modification of Hb-O2 affinity. L35-PMNPs with magnetic field increased tissue PO2 to 27.9 mmHg, without systemic or microhemodynamic changes. These results indicate that localized modification of Hb-O2 affinity can increase PO2 of target tissue without affecting systemic O2 delivery or triggering O2 autoregulation mechanisms. This technology can be used to treat local hypoxia and to

Water-filled balloon in the postoperative resection cavity improves dose distribution to target volumes in radiotherapy of maxillary sinus carcinoma.

PubMed

Zhang, Qun; Lin, Shi-Rong; He, Fang; Kang, De-Hua; Chen, Guo-Zhang; Luo, Wei

2011-11-01

Postoperative radiotherapy is a major treatment for patients with maxillary sinus carcinoma. However, the irregular resection cavity poses a technical difficulty for this treatment, causing uneven dose distribution to target volumes. In this study, we evaluated the dose distribution to target volumes and normal tissues in postoperative intensity-modulated radiotherapy (IMRT) after placing a water-filled balloon into the resection cavity. Three postoperative patients with advanced maxillary sinus carcinoma were selected in this trial. Water-filled balloons and supporting dental stents were fabricated according to the size of the maxillary resection cavity. Simulation CT scans were performed with or without water-filled balloons, IMRT treatment plans were established, and dose distribution to target volumes and organs at risk were evaluated. Compared to those in the treatment plan without balloons, the dose (D98) delivered to 98% of the gross tumor volume (GTV) increased by 2.1 Gy (P = 0.009), homogeneity index (HI) improved by 2.3% (P = 0.001), and target volume conformity index (TCI) of 68 Gy increased by 18.5% (P = 0.011) in the plan with balloons. Dosimetry endpoints of normal tissues around target regions in both plans were not significantly different (P > 0.05) except for the optic chiasm. In the plan without balloons, 68 Gy high-dose regions did not entirely cover target volumes in the ethmoid sinus, posteromedial wall of the maxillary sinus, or surgical margin of the hard palate. In contrast, 68 Gy high-dose regions entirely covered the GTV in the plan with balloons. These results suggest that placing a water-filled balloon in the resection cavity for postoperative IMRT of maxillary sinus carcinoma can reduce low-dose regions and markedly and simultaneously increase dose homogeneity and conformity of target volumes.

Relative binding affinity of carboxylate-, phosphonate-, and bisphosphonate-functionalized gold nanoparticles targeted to damaged bone tissue

NASA Astrophysics Data System (ADS)

Ross, Ryan D.; Cole, Lisa E.; Roeder, Ryan K.

2012-10-01

Functionalized Au NPs have received considerable recent interest for targeting and labeling cells and tissues. Damaged bone tissue can be targeted by functionalizing Au NPs with molecules exhibiting affinity for calcium. Therefore, the relative binding affinity of Au NPs surface functionalized with either carboxylate ( l-glutamic acid), phosphonate (2-aminoethylphosphonic acid), or bisphosphonate (alendronate) was investigated for targeted labeling of damaged bone tissue in vitro. Targeted labeling of damaged bone tissue was qualitatively verified by visual observation and backscattered electron microscopy, and quantitatively measured by the surface density of Au NPs using field-emission scanning electron microscopy. The surface density of functionalized Au NPs was significantly greater within damaged tissue compared to undamaged tissue for each functional group. Bisphosphonate-functionalized Au NPs exhibited a greater surface density labeling damaged tissue compared to glutamic acid- and phosphonic acid-functionalized Au NPs, which was consistent with the results of previous work comparing the binding affinity of the same functionalized Au NPs to synthetic hydroxyapatite crystals. Targeted labeling was enabled not only by the functional groups but also by the colloidal stability in solution. Functionalized Au NPs were stabilized by the presence of the functional groups, and were shown to remain well dispersed in ionic (phosphate buffered saline) and serum (fetal bovine serum) solutions for up to 1 week. Therefore, the results of this study suggest that bisphosphonate-functionalized Au NPs have potential for targeted delivery to damaged bone tissue in vitro and provide motivation for in vivo investigation.

Comparing host and target environments for distributed Ada programs

NASA Technical Reports Server (NTRS)

Paulk, Mark C.

1986-01-01

The Ada programming language provides a means of specifying logical concurrency by using multitasking. Extending the Ada multitasking concurrency mechanism into a physically concurrent distributed environment which imposes its own requirements can lead to incompatibilities. These problems are discussed. Using distributed Ada for a target system may be appropriate, but when using the Ada language in a host environment, a multiprocessing model may be more suitable than retargeting an Ada compiler for the distributed environment. The tradeoffs between multitasking on distributed targets and multiprocessing on distributed hosts are discussed. Comparisons of the multitasking and multiprocessing models indicate different areas of application.

Distribution of toxic alkaloids in tissues from three herbal medicine Aconitum species using laser micro-dissection, UHPLC-QTOF MS and LC-MS/MS techniques.

PubMed

Jaiswal, Yogini; Liang, Zhitao; Ho, Alan; Wong, LaiLai; Yong, Peng; Chen, Hubiao; Zhao, Zhongzhen

2014-11-01

Aconite poisoning continues to be a major type of poisoning caused by herbal drugs in many countries. Nevertheless, despite its toxic characteristics, aconite is used because of its valuable therapeutic benefits. The aim of the present study was to determine the distribution of toxic alkaloids in tissues of aconite roots through chemical profiling. Three species were studied, all being used in traditional Chinese Medicine (TCM) and traditional Indian medicine (Ayurveda), namely: Aconitum carmichaelii, Aconitum kusnezoffii and Aconitum heterophyllum. Laser micro-dissection was used for isolation of target microscopic tissues, such as the metaderm, cortex, xylem, pith, and phloem, with ultra-high performance liquid chromatography equipped with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF MS) employed for detection of metabolites. Using a multi-targeted approach through auto and targeted LC-MS/MS, 48 known compounds were identified and the presence of aconitine, mesaconitine and hypaconitine that are the biomarkers of this plant was confirmed in the tissues. These results suggest that the three selected toxic alkaloids were exclusively found in A. carmichaelii and A. kusnezoffii. The most toxic components were found in large A. carmichaelii roots with more lateral root projections, and specifically in the metaderm, cork and vascular bundle tissues. The results from metabolite profiling were correlated with morphological features to predict the tissue specific distribution of toxic components and toxicity differences among the selected species. By careful exclusion of tissues having toxic diester diterpenoid alkaloids, the beneficial effects of aconite can still be retained and the frequency of toxicity occurrences can be greatly reduced. Knowledge of tissue-specific metabolite distribution can guide users and herbal drug manufacturers in prudent selection of relatively safer and therapeutically more effective parts of the root. The information provided from

TargetMiner: microRNA target prediction with systematic identification of tissue-specific negative examples.

PubMed

Bandyopadhyay, Sanghamitra; Mitra, Ramkrishna

2009-10-15

Prediction of microRNA (miRNA) target mRNAs using machine learning approaches is an important area of research. However, most of the methods suffer from either high false positive or false negative rates. One reason for this is the marked deficiency of negative examples or miRNA non-target pairs. Systematic identification of non-target mRNAs is still not addressed properly, and therefore, current machine learning approaches are compelled to rely on artificially generated negative examples for training. In this article, we have identified approximately 300 tissue-specific negative examples using a novel approach that involves expression profiling of both miRNAs and mRNAs, miRNA-mRNA structural interactions and seed-site conservation. The newly generated negative examples are validated with pSILAC dataset, which elucidate the fact that the identified non-targets are indeed non-targets.These high-throughput tissue-specific negative examples and a set of experimentally verified positive examples are then used to build a system called TargetMiner, a support vector machine (SVM)-based classifier. In addition to assessing the prediction accuracy on cross-validation experiments, TargetMiner has been validated with a completely independent experimental test dataset. Our method outperforms 10 existing target prediction algorithms and provides a good balance between sensitivity and specificity that is not reflected in the existing methods. We achieve a significantly higher sensitivity and specificity of 69% and 67.8% based on a pool of 90 feature set and 76.5% and 66.1% using a set of 30 selected feature set on the completely independent test dataset. In order to establish the effectiveness of the systematically generated negative examples, the SVM is trained using a different set of negative data generated using the method in Yousef et al. A significantly higher false positive rate (70.6%) is observed when tested on the independent set, while all other factors are kept the

Tissue distribution of co-planar and non-planar tetra- and hexa-chlorobiphenyl isomers in guinea pigs after oral ingestion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jan, J.; Logar, B.; Jan, J.

1996-03-01

Food ingestion is the most important route for the uptake of lipophilic organochlorine contaminants. Uptake and transfer of the contaminants from the digestive tract to target organs can be used for risk evaluation. The bioconcentration and migration of polychlorobiphenyls (PCBs) is highly structure - dependent. Bioconcentration is correlated with lipophilicity on the basis of the n-octanol/water partition coefficient in its logarithmic form - logKow. However, some factors e.g. diffusion through cell membranes, accumulation in specific organs and tissues, uptake and deputation kinetics and metabolism can also influence the bioconcentration. Individual PCB compounds of commercial PCB preparation are taken up bymore » organisms to markedly different extents. Until now little is known about the distribution of non-planar and co-planar PCBs in different tissues. Co-planar PCBs have dioxin - like toxicity. This study examines differences in the bioconcentration of two pairs of tetra and hexa chlorobiphenyls from the digestive tract and their distribution in different tissues of guinea pigs.« less

Targeted metabolomic profiling in rat tissues reveals sex differences.

PubMed

Ruoppolo, Margherita; Caterino, Marianna; Albano, Lucia; Pecce, Rita; Di Girolamo, Maria Grazia; Crisci, Daniela; Costanzo, Michele; Milella, Luigi; Franconi, Flavia; Campesi, Ilaria

2018-03-16

Sex differences affect several diseases and are organ-and parameter-specific. In humans and animals, sex differences also influence the metabolism and homeostasis of amino acids and fatty acids, which are linked to the onset of diseases. Thus, the use of targeted metabolite profiles in tissues represents a powerful approach to examine the intermediary metabolism and evidence for any sex differences. To clarify the sex-specific activities of liver, heart and kidney tissues, we used targeted metabolomics, linear discriminant analysis (LDA), principal component analysis (PCA), cluster analysis and linear correlation models to evaluate sex and organ-specific differences in amino acids, free carnitine and acylcarnitine levels in male and female Sprague-Dawley rats. Several intra-sex differences affect tissues, indicating that metabolite profiles in rat hearts, livers and kidneys are organ-dependent. Amino acids and carnitine levels in rat hearts, livers and kidneys are affected by sex: male and female hearts show the greatest sexual dimorphism, both qualitatively and quantitatively. Finally, multivariate analysis confirmed the influence of sex on the metabolomics profiling. Our data demonstrate that the metabolomics approach together with a multivariate approach can capture the dynamics of physiological and pathological states, which are essential for explaining the basis of the sex differences observed in physiological and pathological conditions.

Temperature distributions in tissues during local hyperthermia by stationary or steered beams of unfocused or focused ultrasound.

PubMed Central

Lele, P. P.; Parker, K. J.

1982-01-01

Temperature distributions resulting from insonation with stationary or steered beams of unfocused or focused ultrasound were measured in tissue-equivalent phantom, beef muscle in vitro, dog muscle mass, and transplanted murine tumours in vivo. Arrays of 4 to 6 thermocouples stepped through the volume of interest under computer control were used to measure the steady-state temperatures at 600 to 800 locations in both in vitro and in vivo experiments. The results were confirmed in spontaneous tumours in dog patients using fewer multi-thermocouple probes. Plane wave ultrasound was found to result in spatially non-uniform hyperthermia even in superficial tumours. The region of maximum temperature rise was small in extent and was situated at a depth which varied in the different models from 0.5 to 1.0 cm. Neither its location nor its extent could be varied by spatial manipulations of the transducer or by changing the insonation parameters except the ultrasonic frequency. A second region of hyperthermia was produced at depth by reflective heating if an ultrasonically reflective target, such as bone or air-containing tissue, was located below the target tissue. On the other hand, using available steered, focused ultrasound techniques, tumours (whether situated superficially or at depth) could be heated to a uniform, controllable temperature without undesirable temperature elevation in surrounding normal tissues. The use of steered, focused ultrasound permits deposition of energy to be tailored to the specific needs of each individual tumour. The small size of the focal region enables heating of tumours even when located near ultrasound reflecting targets. PMID:6950746

Quantum partial search for uneven distribution of multiple target items

NASA Astrophysics Data System (ADS)

Zhang, Kun; Korepin, Vladimir

2018-06-01

Quantum partial search algorithm is an approximate search. It aims to find a target block (which has the target items). It runs a little faster than full Grover search. In this paper, we consider quantum partial search algorithm for multiple target items unevenly distributed in a database (target blocks have different number of target items). The algorithm we describe can locate one of the target blocks. Efficiency of the algorithm is measured by number of queries to the oracle. We optimize the algorithm in order to improve efficiency. By perturbation method, we find that the algorithm runs the fastest when target items are evenly distributed in database.

Tissue distribution and toxicity effects of myclobutanil enantiomers in lizards (Eremias argus).

PubMed

Chen, Li; Li, Ruiting; Diao, Jinling; Tian, Zhongnan; Di, Shanshan; Zhang, Wenjun; Cheng, Cheng; Zhou, Zhiqiang

2017-11-01

In recent years, serious environmental pollution has caused a decrease in the abundance of many species worldwide. Reptiles are the most diverse group of terrestrial vertebrates. There are large amounts of toxicological data available regarding myclobutanil, but the adverse effects of myclobutanil on lizards has not been widely reported. In this study, treatment groups were orally administered a single-dose of myclobutanil (20mg/kg body weight (bw)). Subsequently, it was found that there were differences in myclobutanil levels between the different tissues and concentrations also changed with degradation time. The tissue concentrations of myclobutanil decreased in the order of: stomach > liver > lung > blood > testis > kidney > heart > brain. Based on our results, the liver and testis were considered to be the main target organs in lizards, indicating that the myclobutanil could induce potential hepatic and reproductive toxicity on lizards. Meanwhile, it was also demonstrated that the toxic effects of myclobutanil was different in different species, and the distribution of different pesticides in lizards were different. Copyright © 2017. Published by Elsevier Inc.

Gene Delivery to Adipose Tissue Using Transcriptionally Targeted rAAV8 Vectors

PubMed Central

Uhrig-Schmidt, Silke; Geiger, Matthias; Luippold, Gerd; Birk, Gerald; Mennerich, Detlev; Neubauer, Heike; Grimm, Dirk; Wolfrum, Christian; Kreuz, Sebastian

2014-01-01

In recent years, the increasing prevalence of obesity and obesity-related co-morbidities fostered intensive research in the field of adipose tissue biology. To further unravel molecular mechanisms of adipose tissue function, genetic tools enabling functional studies in vitro and in vivo are essential. While the use of transgenic animals is well established, attempts using viral and non-viral vectors to genetically modify adipocytes in vivo are rare. Therefore, we here characterized recombinant Adeno-associated virus (rAAV) vectors regarding their potency as gene transfer vehicles for adipose tissue. Our results demonstrate that a single dose of systemically applied rAAV8-CMV-eGFP can give rise to remarkable transgene expression in murine adipose tissues. Upon transcriptional targeting of the rAAV8 vector to adipocytes using a 2.2 kb fragment of the murine adiponectin (mAP2.2) promoter, eGFP expression was significantly decreased in off-target tissues while efficient transduction was maintained in subcutaneous and visceral fat depots. Moreover, rAAV8-mAP2.2-mediated expression of perilipin A – a lipid-droplet-associated protein – resulted in significant changes in metabolic parameters only three weeks post vector administration. Taken together, our findings indicate that rAAV vector technology is applicable as a flexible tool to genetically modify adipocytes for functional proof-of-concept studies and the assessment of putative therapeutic targets in vivo. PMID:25551639

Transferrin receptors in human tissues: their distribution and possible clinical relevance.

PubMed

Gatter, K C; Brown, G; Trowbridge, I S; Woolston, R E; Mason, D Y

1983-05-01

The distribution of transferrin receptors (TR) has been studied in a range of normal and malignant tissues using four monoclonal antibodies, BK19.9, B3/25, T56/14 and T58/1. In normal tissues TR was found in a limited number of sites, notably basal epidermis, the endocrine pancreas, hepatocytes, Kupffer cells, testis and pituitary. This restricted pattern of distribution may be relevant to the characteristic pattern of iron deposition in primary haemachromatosis. In contrast to this limited pattern of expression in normal tissue, the receptor was widely distributed in carcinomas, sarcomas and in samples from cases of Hodgkin's disease. This malignancy-associated expression of the receptor may play a role in the anaemia of advanced malignancy by competing with the bone marrow for serum iron.

Transferrin receptors in human tissues: their distribution and possible clinical relevance.

PubMed Central

Gatter, K C; Brown, G; Trowbridge, I S; Woolston, R E; Mason, D Y

1983-01-01

The distribution of transferrin receptors (TR) has been studied in a range of normal and malignant tissues using four monoclonal antibodies, BK19.9, B3/25, T56/14 and T58/1. In normal tissues TR was found in a limited number of sites, notably basal epidermis, the endocrine pancreas, hepatocytes, Kupffer cells, testis and pituitary. This restricted pattern of distribution may be relevant to the characteristic pattern of iron deposition in primary haemachromatosis. In contrast to this limited pattern of expression in normal tissue, the receptor was widely distributed in carcinomas, sarcomas and in samples from cases of Hodgkin's disease. This malignancy-associated expression of the receptor may play a role in the anaemia of advanced malignancy by competing with the bone marrow for serum iron. Images PMID:6302135

Modelling PET radionuclide production in tissue and external targets using Geant4

NASA Astrophysics Data System (ADS)

Amin, T.; Infantino, A.; Lindsay, C.; Barlow, R.; Hoehr, C.

2017-07-01

The Proton Therapy Facility in TRIUMF provides 74 MeV protons extracted from a 500 MeV H- cyclotron for ocular melanoma treatments. During treatment, positron emitting radionuclides such as 1C, 15O and 13N are produced in patient tissue. Using PET scanners, the isotopic activity distribution can be measured for in-vivo range verification. A second cyclotron, the TR13, provides 13 MeV protons onto liquid targets for the production of PET radionuclides such as 18F, 13N or 68Ga, for medical applications. The aim of this work was to validate Geant4 against FLUKA and experimental measurements for production of the above-mentioned isotopes using the two cyclotrons. The results show variable degrees of agreement. For proton therapy, the proton-range agreement was within 2 mm for 11C activity, whereas 13N disagreed. For liquid targets at the TR13 the average absolute deviation ratio between FLUKA and experiment was 1.9±2.7, whereas the average absolute deviation ratio between Geant4 and experiment was 0. 6±0.4. This is due to the uncertainties present in experimentally determined reaction cross sections.

The inclusion of capillary distribution in the adiabatic tissue homogeneity model of blood flow

NASA Astrophysics Data System (ADS)

Koh, T. S.; Zeman, V.; Darko, J.; Lee, T.-Y.; Milosevic, M. F.; Haider, M.; Warde, P.; Yeung, I. W. T.

2001-05-01

We have developed a non-invasive imaging tracer kinetic model for blood flow which takes into account the distribution of capillaries in tissue. Each individual capillary is assumed to follow the adiabatic tissue homogeneity model. The main strength of our new model is in its ability to quantify the functional distribution of capillaries by the standard deviation in the time taken by blood to pass through the tissue. We have applied our model to the human prostate and have tested two different types of distribution functions. Both distribution functions yielded very similar predictions for the various model parameters, and in particular for the standard deviation in transit time. Our motivation for developing this model is the fact that the capillary distribution in cancerous tissue is drastically different from in normal tissue. We believe that there is great potential for our model to be used as a prognostic tool in cancer treatment. For example, an accurate knowledge of the distribution in transit times might result in an accurate estimate of the degree of tumour hypoxia, which is crucial to the success of radiation therapy.

Calculation of Absorbed Dose in Target Tissue and Equivalent Dose in Sensitive Tissues of Patients Treated by BNCT Using MCNP4C

NASA Astrophysics Data System (ADS)

Zamani, M.; Kasesaz, Y.; Khalafi, H.; Pooya, S. M. Hosseini

Boron Neutron Capture Therapy (BNCT) is used for treatment of many diseases, including brain tumors, in many medical centers. In this method, a target area (e.g., head of patient) is irradiated by some optimized and suitable neutron fields such as research nuclear reactors. Aiming at protection of healthy tissues which are located in the vicinity of irradiated tissue, and based on the ALARA principle, it is required to prevent unnecessary exposure of these vital organs. In this study, by using numerical simulation method (MCNP4C Code), the absorbed dose in target tissue and the equiavalent dose in different sensitive tissues of a patiant treated by BNCT, are calculated. For this purpose, we have used the parameters of MIRD Standard Phantom. Equiavelent dose in 11 sensitive organs, located in the vicinity of target, and total equivalent dose in whole body, have been calculated. The results show that the absorbed dose in tumor and normal tissue of brain equal to 30.35 Gy and 0.19 Gy, respectively. Also, total equivalent dose in 11 sensitive organs, other than tumor and normal tissue of brain, is equal to 14 mGy. The maximum equivalent doses in organs, other than brain and tumor, appear to the tissues of lungs and thyroid and are equal to 7.35 mSv and 3.00 mSv, respectively.

Ligand-targeted delivery of small interfering RNAs to malignant cells and tissues.

PubMed

Thomas, Mini; Kularatne, Sumith A; Qi, Longwu; Kleindl, Paul; Leamon, Christopher P; Hansen, Michael J; Low, Philip S

2009-09-01

Potential clinical applications of small interfering RNA (siRNA) are hampered primarily by delivery issues. We have successfully addressed the delivery problems associated with off-site targeting of highly toxic chemotherapeutic agents by attaching the drugs to tumor-specific ligands that will carry the attached cargo into the desired cancer cell. Indeed, several such tumor-targeted drugs are currently undergoing human clinical trials. We now show that efficient targeting of siRNA to malignant cells and tissues can be achieved by covalent conjugation of small-molecular-weight, high-affinity ligands, such as folic acid and DUPA (2-[3-(1, 3-dicarboxy propyl)-ureido] pentanedioic acid), to siRNA. The former ligand binds a folate receptor that is overexpressed on a variety of cancers, whereas the latter ligand binds to prostate-specific membrane antigen that is overexpressed specifically on prostate cancers and the neovasculature of all solid tumors. Using these ligands, we show remarkable receptor-mediated targeting of siRNA to cancer tissues in vitro and in vivo.

Simultaneous determination of aditoprim and its three major metabolites in pigs, broilers and carp tissues, and its application in tissue distribution and depletion studies.

PubMed

Wang, Liye; Huang, Lingli; Pan, Yuanhu; Wu, Qinghua; Xie, Shuyu; Yuan, Zonghui

2016-08-01

Aditoprim (ADP) is a recently developed dihydrofolate reductase inhibitor that has shown promise for therapeutic use in veterinary medicine because of its excellent pharmacokinetic properties. In this study, a sensitive and reliable multi-residue chromatography-ultraviolet (HPLC-UV) method for the quantitative analysis of ADP and its three major metabolites was developed, and the tissue distribution and depletion profiles of ADP and its major metabolites in pigs, broilers and carp were investigated. Edible and additional tissues (heart, lung, stomach, intestine and swim bladder) were collected for analysis at six different withdrawal periods after ADP administration for 7 days. ADP, N-monomethyl-ADP and N-didesmethyl-ADP were detected in almost all tissues in the three species. The liver, kidney and lung showed higher residue concentrations, and the liver showed a longer residue half-life (t1/2) than other tissues. In the liver, ADP was the most abundant component with the longest persistence. The results suggest that the liver was the residual target tissue and ADP was the marker residue, and the conclusive withdrawal time (WDT) of 20 days in pigs, 16 days in broilers and 25 days in carp was estimated using the assessment methodologies approved by the Joint FAO/WHO Expert Committee on Food Additives (JECFA).

Visualisation of the distributions of melanin and indocyanine green in biological tissues

DOE Office of Scientific and Technical Information (OSTI.GOV)

Genina, E A; Fedosov, I V; Bashkatov, A N

2008-03-31

A double-wavelength laser scanning microphotometer with the high spectral and spatial resolutions is developed for studying the distribution of endogenic and exogenic dyes in biological tissues. Samples of hair and skin biopsy with hair follicles stained with indocyanine green are studied. The spatial distribution of indocyanine green and melanin in the biological tissue is determined from the measured optical transmittance. (laser biology)

Diannexin Protects against Renal Ischemia Reperfusion Injury and Targets Phosphatidylserines in Ischemic Tissue

PubMed Central

Wever, Kimberley E.; Wagener, Frank A. D. T. G.; Frielink, Cathelijne; Boerman, Otto C.; Scheffer, Gert J.; Allison, Anthony; Masereeuw, Rosalinde; Rongen, Gerard A.

2011-01-01

Renal ischemia/reperfusion injury (IRI) frequently complicates shock, renal transplantation and cardiac and aortic surgery, and has prognostic significance. The translocation of phosphatidylserines to cell surfaces is an important pro-inflammatory signal for cell-stress after IRI. We hypothesized that shielding of exposed phosphatidylserines by the annexin A5 (ANXA5) homodimer Diannexin protects against renal IRI. Protective effects of Diannexin on the kidney were studied in a mouse model of mild renal IRI. Diannexin treatment before renal IRI decreased proximal tubule damage and leukocyte influx, decreased transcription and expression of renal injury markers Neutrophil Gelatinase Associated Lipocalin and Kidney Injury Molecule-1 and improved renal function. A mouse model of ischemic hind limb exercise was used to assess Diannexin biodistribution and targeting. When comparing its biodistribution and elimination to ANXA5, Diannexin was found to have a distinct distribution pattern and longer blood half-life. Diannexin targeted specifically to the ischemic muscle and its affinity exceeded that of ANXA5. Targeting of both proteins was inhibited by pre-treatment with unlabeled ANXA5, suggesting that Diannexin targets specifically to ischemic tissues via phosphatidylserine-binding. This study emphasizes the importance of phosphatidylserine translocation in the pathophysiology of IRI. We show for the first time that Diannexin protects against renal IRI, making it a promising therapeutic tool to prevent IRI in a clinical setting. Our results indicate that Diannexin is a potential new imaging agent for the study of phosphatidylserine-exposing organs in vivo. PMID:21918686

Target mass effects in parton quasi-distributions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Radyushkin, A. V.

We study the impact of non-zero (and apparently large) value of the nucleon mass M on the shape of parton quasi-distributions Q(y,p 3), in particular on its change with the change of the nucleon momentum p 3. We observe that the usual target-mass corrections induced by the M-dependence of the twist-2 operators are rather small. Moreover, we show that within the framework based on parametrizations by transverse momentum dependent distribution functions (TMDs) these corrections are canceled by higher-twist contributions. Lastly, we identify a novel source of kinematic target-mass dependence of TMDs and build models corrected for such dependence. We findmore » that resulting changes may be safely neglected for p 3≳2M.« less

Target mass effects in parton quasi-distributions

DOE PAGES

Radyushkin, A. V.

2017-05-11

We study the impact of non-zero (and apparently large) value of the nucleon mass M on the shape of parton quasi-distributions Q(y,p 3), in particular on its change with the change of the nucleon momentum p 3. We observe that the usual target-mass corrections induced by the M-dependence of the twist-2 operators are rather small. Moreover, we show that within the framework based on parametrizations by transverse momentum dependent distribution functions (TMDs) these corrections are canceled by higher-twist contributions. Lastly, we identify a novel source of kinematic target-mass dependence of TMDs and build models corrected for such dependence. We findmore » that resulting changes may be safely neglected for p 3≳2M.« less

Microdialysis as a way to measure antibiotics concentration in tissues.

PubMed

Marchand, Sandrine; Chauzy, Alexia; Dahyot-Fizelier, Claire; Couet, William

2016-09-01

As for all other drugs, antibiotics must reach their pharmacodynamic target in order to exert their effect, but because infection may occur in various tissues the distribution of antibiotics has always been of particular concern. In this article, we will first critically review the various methodologies available to study antibiotics tissue distribution, including microdialysis, secondly we will show how basic pharmacokinetic concepts may help to predict or interpret antibiotics tissue distribution and third we will address the question of linking antibiotics tissue distribution with their antimicrobial effect, using modern pharmacokinetic-pharmacodynamic methods. Copyright © 2016 Elsevier Ltd. All rights reserved.

Distributed Peer-to-Peer Target Tracking in Wireless Sensor Networks

PubMed Central

Wang, Xue; Wang, Sheng; Bi, Dao-Wei; Ma, Jun-Jie

2007-01-01

Target tracking is usually a challenging application for wireless sensor networks (WSNs) because it is always computation-intensive and requires real-time processing. This paper proposes a practical target tracking system based on the auto regressive moving average (ARMA) model in a distributed peer-to-peer (P2P) signal processing framework. In the proposed framework, wireless sensor nodes act as peers that perform target detection, feature extraction, classification and tracking, whereas target localization requires the collaboration between wireless sensor nodes for improving the accuracy and robustness. For carrying out target tracking under the constraints imposed by the limited capabilities of the wireless sensor nodes, some practically feasible algorithms, such as the ARMA model and the 2-D integer lifting wavelet transform, are adopted in single wireless sensor nodes due to their outstanding performance and light computational burden. Furthermore, a progressive multi-view localization algorithm is proposed in distributed P2P signal processing framework considering the tradeoff between the accuracy and energy consumption. Finally, a real world target tracking experiment is illustrated. Results from experimental implementations have demonstrated that the proposed target tracking system based on a distributed P2P signal processing framework can make efficient use of scarce energy and communication resources and achieve target tracking successfully.

Three-Dimensionally Engineered Normal Human Lung Tissue-Like Assemblies: Target Tissues for Human Respiratory Viral Infections

NASA Technical Reports Server (NTRS)

Goodwin, Thomas J.; McCarthy, M.; Lin, Y-H.; Deatly, A. M.

2008-01-01

In vitro three-dimensional (3D) human lung epithelio-mesenchymal tissue-like assemblies (3D hLEM TLAs) from this point forward referred to as TLAs were engineered in Rotating Wall Vessel (RWV) technology to mimic the characteristics of in vivo tissues thus providing a tool to study human respiratory viruses and host cell interactions. The TLAs were bioengineered onto collagen-coated cyclodextran microcarriers using primary human mesenchymal bronchial-tracheal cells (HBTC) as the foundation matrix and an adult human bronchial epithelial immortalized cell line (BEAS-2B) as the overlying component. The resulting TLAs share significant characteristics with in vivo human respiratory epithelium including polarization, tight junctions, desmosomes, and microvilli. The presence of tissue-like differentiation markers including villin, keratins, and specific lung epithelium markers, as well as the production of tissue mucin, further confirm these TLAs differentiated into tissues functionally similar to in vivo tissues. Increasing virus titers for human respiratory syncytial virus (wtRSVA2) and the detection of membrane bound glycoproteins over time confirm productive infection with the virus. Therefore, we assert TLAs mimic aspects of the human respiratory epithelium and provide a unique capability to study the interactions of respiratory viruses and their primary target tissue independent of the host s immune system.

Uptake, tissue distribution, and metabolism of malachite green in the channel catfish (Ictalurus punctatus)

USGS Publications Warehouse

Plakas, S.M.; El Said, K. R.; Stehly, G.R.; Gingerich, W.H.; Allen, J.L.

1996-01-01

The disposition of malachite green was determined in channel catfish (Ictalurus punctatus) after intravascular dosing (0.8 mg . Kg-1) or waterborne exposure (0.8 mg . L-1 for 1 h). After intravascular dosing, mean plasma concentrations of the parent compound exhibited a triphasic decline with a terminal elimination half-life of 6.2 h. Malachite green was rapidly absorbed and concentrated in the tissues during waterborne exposure. The rate of accumulation was directly related to pH of the exposure water. After waterborne exposure, elimination of the parent compound from plasma also was triphasic with a terminal half-life of 4.7 h. In muscle, the half-life of the parent compound was approximately 67 h. Malachite green and its metabolites were widely distributed in all tissues. In fish exposed to C-14-labeled malachite green, total drug equivalent concentrations were highest in abdominal fat and lowest in plasma. Malachite green was rapidly and extensively metabolized to its reduced form, leucomalachite green, which was slowly eliminated from the tissues. Leucomalachite green is an appropriate target analyte for monitoring exposure of channel catfish to this drug.

Therapeutic analysis of high-dose-rate {sup 192}Ir vaginal cuff brachytherapy for endometrial cancer using a cylindrical target volume model and varied cancer cell distributions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Hualin, E-mail: hualin.zhang@northwestern.edu; Donnelly, Eric D.; Strauss, Jonathan B.

Purpose: To evaluate high-dose-rate (HDR) vaginal cuff brachytherapy (VCBT) in the treatment of endometrial cancer in a cylindrical target volume with either a varied or a constant cancer cell distributions using the linear quadratic (LQ) model. Methods: A Monte Carlo (MC) technique was used to calculate the 3D dose distribution of HDR VCBT over a variety of cylinder diameters and treatment lengths. A treatment planning system (TPS) was used to make plans for the various cylinder diameters, treatment lengths, and prescriptions using the clinical protocol. The dwell times obtained from the TPS were fed into MC. The LQ model wasmore » used to evaluate the therapeutic outcome of two brachytherapy regimens prescribed either at 0.5 cm depth (5.5 Gy × 4 fractions) or at the vaginal mucosal surface (8.8 Gy × 4 fractions) for the treatment of endometrial cancer. An experimentally determined endometrial cancer cell distribution, which showed a varied and resembled a half-Gaussian distribution, was used in radiobiology modeling. The equivalent uniform dose (EUD) to cancer cells was calculated for each treatment scenario. The therapeutic ratio (TR) was defined by comparing VCBT with a uniform dose radiotherapy plan in term of normal cell survival at the same level of cancer cell killing. Calculations of clinical impact were run twice assuming two different types of cancer cell density distributions in the cylindrical target volume: (1) a half-Gaussian or (2) a uniform distribution. Results: EUDs were weakly dependent on cylinder size, treatment length, and the prescription depth, but strongly dependent on the cancer cell distribution. TRs were strongly dependent on the cylinder size, treatment length, types of the cancer cell distributions, and the sensitivity of normal tissue. With a half-Gaussian distribution of cancer cells which populated at the vaginal mucosa the most, the EUDs were between 6.9 Gy × 4 and 7.8 Gy × 4, the TRs were in the range from (5.0){sup 4} to

Uptake, tissue distribution and depuration of triclosan in the guppy Poecilia vivipara acclimated to freshwater.

PubMed

Escarrone, Ana Laura Venquiaruti; Caldas, Sergiane Souza; Primel, Ednei Gilberto; Martins, Samantha Eslava; Nery, Luiz Eduardo Maia

2016-08-01

The agent triclosan has been extensively used in different personal care products as a broad-spectrum antimicrobial and preservative agent. Due to its continuous release into the environment, including discharge via wastewater treatment plants, triclosan has been widely detected in aquatic environments. There is growing interest in improving the knowledge about the environmental fate of triclosan due to its possible bioaccumulation and the toxicity it may pose to organisms, such as fish and other non-target species. To investigate the distribution and bioconcentration of triclosan in fish, Poecilia vivipara was exposed to 0.2mgL(-1). Contents of triclosan in whole fish, brain, gonads, liver, muscle and gills were quantified by LC-MS/MS. When lipid normalised concentration was used, the liver exhibited the highest concentration followed by the gills, gonads, brain and muscle tissues. Bioconcentration was increased with time reaching a steady-state around 7-14days for most all tissues. After 24h depuration, triclosan concentrations declined >80% in all tissues except liver, in which triclosan takes longer to be depurated. These results not only clearly indicate that triclosan accumulated in P. vivipara, with tissue-specific bioconcentration factors (BCF) that ranged from 40.2 to 1025.4, but also show that the elimination of triclosan after transferring the fish to triclosan-free freshwater is rapid in all tissues. Copyright © 2016 Elsevier B.V. All rights reserved.

Degree of target utilization influences the location of movement endpoint distributions.

PubMed

Slifkin, Andrew B; Eder, Jeffrey R

2017-03-01

According to dominant theories of motor control, speed and accuracy are optimized when, on the average, movement endpoints are located at the target center and when the variability of the movement endpoint distributions is matched to the width of the target (viz., Meyer, Abrams, Kornblum, Wright, & Smith, 1988). The current study tested those predictions. According to the speed-accuracy trade-off, expanding the range of variability to the amount permitted by the limits of the target boundaries allows for maximization of movement speed while centering the distribution on the target center prevents movement errors that would have occurred had the distribution been off center. Here, participants (N=20) were required to generate 100 consecutive targeted hand movements under each of 15 unique conditions: There were three movement amplitude requirements (80, 160, 320mm) and within each there were five target widths (5, 10, 20, 40, 80mm). According to the results, it was only at the smaller target widths (5, 10mm) that movement endpoint distributions were centered on the target center and the range of movement endpoint variability matched the range specified by the target boundaries. As target width increased (20, 40, 80mm), participants increasingly undershot the target center and the range of movement endpoint variability increasingly underestimated the variability permitted by the target region. The degree of target center undershooting was strongly predicted by the difference between the size of the target and the amount of movement endpoint variability, i.e., the amount of unused space in the target. The results suggest that participants have precise knowledge of their variability relative to that permitted by the target, and they use that knowledge to systematically reduce the travel distance to targets. The reduction in travel distance across the larger target widths might have resulted in greater cost savings than those associated with increases in speed

Distribution of the anticancer drugs doxorubicin, mitoxantrone and topotecan in tumors and normal tissues.

PubMed

Patel, Krupa J; Trédan, Olivier; Tannock, Ian F

2013-07-01

Pharmacokinetic analyses estimate the mean concentration of drug within a given tissue as a function of time, but do not give information about the spatial distribution of drugs within that tissue. Here, we compare the time-dependent spatial distribution of three anticancer drugs within tumors, heart, kidney, liver and brain. Mice bearing various xenografts were treated with doxorubicin, mitoxantrone or topotecan. At various times after injection, tumors and samples of heart, kidney, liver and brain were excised. Within solid tumors, the distribution of doxorubicin, mitoxantrone and topotecan was limited to perivascular regions at 10 min after administration and the distance from blood vessels at which drug intensity fell to half was ~25-75 μm. Although drug distribution improved after 3 and 24 h, there remained a significant decrease in drug fluorescence with increasing distance from tumor blood vessels. Drug distribution was relatively uniform in the heart, kidney and liver with substantially greater perivascular drug uptake than in tumors. There was significantly higher total drug fluorescence in the liver than in tumors after 10 min, 3 and 24 h. Little to no drug fluorescence was observed in the brain. There are marked differences in the spatial distributions of three anticancer drugs within tumor tissue and normal tissues over time, with greater exposure to most normal tissues and limited drug distribution to many cells in tumors. Studies of the spatial distribution of drugs are required to complement pharmacokinetic data in order to better understand and predict drug effects and toxicities.

Pre- and postoperative radiotherapy for extremity soft tissue sarcoma: Evaluation of inter-observer target volume contouring variability among French sarcoma group radiation oncologists.

PubMed

Sargos, P; Charleux, T; Haas, R L; Michot, A; Llacer, C; Moureau-Zabotto, L; Vogin, G; Le Péchoux, C; Verry, C; Ducassou, A; Delannes, M; Mervoyer, A; Wiazzane, N; Thariat, J; Sunyach, M P; Benchalal, M; Laredo, J D; Kind, M; Gillon, P; Kantor, G

2018-04-01

The purpose of this study was to evaluate, during a national workshop, the inter-observer variability in target volume delineation for primary extremity soft tissue sarcoma radiation therapy. Six expert sarcoma radiation oncologists (members of French Sarcoma Group) received two extremity soft tissue sarcoma radiation therapy cases 1: one preoperative and one postoperative. They were distributed with instructions for contouring gross tumour volume or reconstructed gross tumour volume, clinical target volume and to propose a planning target volume. The preoperative radiation therapy case was a patient with a grade 1 extraskeletal myxoid chondrosarcoma of the thigh. The postoperative case was a patient with a grade 3 pleomorphic undifferentiated sarcoma of the thigh. Contour agreement analysis was performed using kappa statistics. For the preoperative case, contouring agreement regarding GTV, gross tumour volume GTV, clinical target volume and planning target volume were substantial (kappa between 0.68 and 0.77). In the postoperative case, the agreement was only fair for reconstructed gross tumour volume (kappa: 0.38) but moderate for clinical target volume and planning target volume (kappa: 0.42). During the workshop discussion, consensus was reached on most of the contour divergences especially clinical target volume longitudinal extension. The determination of a limited cutaneous cover was also discussed. Accurate delineation of target volume appears to be a crucial element to ensure multicenter clinical trial quality assessment, reproducibility and homogeneity in delivering RT. radiation therapy RT. Quality assessment process should be proposed in this setting. We have shown in our study that preoperative radiation therapy of extremity soft tissue sarcoma has less inter-observer contouring variability. Copyright © 2018 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

Investigations of the Cavitation and Damage Thresholds of Histotripsy and Applications in Targeted Tissue Ablation

NASA Astrophysics Data System (ADS)

Vlaisavljevich, Eli

Histotripsy is a noninvasive ultrasound therapy that controls acoustic cavitation to mechanically fractionate soft tissue. This dissertation investigates the physical thresholds to initiate cavitation and produce tissue damage in histotripsy and factors affecting these thresholds in order to develop novel strategies for targeted tissue ablation. In the first part of this dissertation, the effects of tissue properties on histotripsy cavitation thresholds and damage thresholds were investigated. Results demonstrated that the histotripsy shock scattering threshold using multi-cycle pulses increases in stiffer tissues, while the histotripsy intrinsic threshold using single-cycle pulses is independent of tissue stiffness. Further, the intrinsic threshold slightly decreases with lower frequencies and significantly decreases with increasing temperature. The effects of tissue properties on the susceptibility to histotripsy-induced tissue damage were also investigated, demonstrating that stiffer tissues are more resistant to histotripsy. Two strategies were investigated for increasing the effectiveness of histotripsy for the treatment of stiffer tissues, with results showing that thermal preconditioning may be used to alter tissue susceptibility to histotripsy and that lower frequency treatments may increase the efficiency of histotripsy tissue ablation due to enhanced bubble expansion. In the second part of this dissertation, the feasibility of using histotripsy for targeted liver ablation was investigated in an intact in vivo porcine model, with results demonstrating that histotripsy was capable of non-invasively creating precise lesions throughout the entire liver. Additionally, a tissue selective ablation approach was developed, where histotripsy completely fractionated the liver tissue surrounding the major hepatic vessels and gallbladder while being self-limited at the boundaries of these critical structures. Finally, the long-term effects of histotripsy liver

Design, construction and performance evaluation of the target tissue thickness measurement system in intraoperative radiotherapy for breast cancer

NASA Astrophysics Data System (ADS)

Yazdani, Mohammad Reza; Setayeshi, Saeed; Arabalibeik, Hossein; Akbari, Mohammad Esmaeil

2017-05-01

Intraoperative electron radiation therapy (IOERT), which uses electron beams for irradiating the target directly during the surgery, has the advantage of delivering a homogeneous dose to a controlled layer of tissue. Since the dose falls off quickly below the target thickness, the underlying normal tissues are spared. In selecting the appropriate electron energy, the accuracy of the target tissue thickness measurement is critical. In contrast to other procedures applied in IOERT, the routine measurement method is considered to be completely traditional and approximate. In this work, a novel mechanism is proposed for measuring the target tissue thickness with an acceptable level of accuracy. An electronic system has been designed and manufactured with the capability of measuring the tissue thickness based on the recorded electron density under the target. The results indicated the possibility of thickness measurement with a maximum error of 2 mm for 91.35% of data. Aside from system limitation in estimating the thickness of 5 mm phantom, for 88.94% of data, maximum error is 1 mm.

External calibration of polarimetric radar images using distributed targets

NASA Technical Reports Server (NTRS)

Yueh, Simon H.; Nghiem, S. V.; Kwok, R.

1992-01-01

A new technique is presented for calibrating polarimetric synthetic aperture radar (SAR) images using only the responses from natural distributed targets. The model for polarimetric radars is assumed to be X = cRST where X is the measured scattering matrix corresponding to the target scattering matrix S distorted by the system matrices T and R (in general T does not equal R(sup t)). To allow for the polarimetric calibration using only distributed targets and corner reflectors, van Zyl assumed a reciprocal polarimetric radar model with T = R(sup t); when applied for JPL SAR data, a heuristic symmetrization procedure is used by POLCAL to compensate the phase difference between the measured HV and VH responses and then take the average of both. This heuristic approach causes some non-removable cross-polarization responses for corner reflectors, which can be avoided by a rigorous symmetrization method based on reciprocity. After the radar is made reciprocal, a new algorithm based on the responses from distributed targets with reflection symmetry is developed to estimate the cross-talk parameters. The new algorithm never experiences problems in convergence and is also found to converge faster than the existing routines implemented for POLCAL. When the new technique is implemented for the JPL polarimetric data, symmetrization and cross-talk removal are performed on a line-by-line (azimuth) basis. After the cross-talks are removed from the entire image, phase and amplitude calibrations are carried out by selecting distributed targets either with azimuthal symmetry along the looking direction or with some well-known volume and surface scattering mechanisms to estimate the relative phases and amplitude responses of the horizontal and vertical channels.

Multiwaveguide implantable probe for light delivery to sets of distributed brain targets.

PubMed

Zorzos, Anthony N; Boyden, Edward S; Fonstad, Clifton G

2010-12-15

Optical fibers are commonly inserted into living tissues such as the brain in order to deliver light to deep targets for neuroscientific and neuroengineering applications such as optogenetics, in which light is used to activate or silence neurons expressing specific photosensitive proteins. However, an optical fiber is limited to delivering light to a single target within the three-dimensional structure of the brain. We here demonstrate a multiwaveguide probe capable of independently delivering light to multiple targets along the probe axis, thus enabling versatile optical control of sets of distributed brain targets. The 1.45-cm-long probe is microfabricated in the form of a 360-μm-wide array of 12 parallel silicon oxynitride (SiON) multimode waveguides clad with SiO(2) and coated with aluminum; probes of custom dimensions are easily created as well. The waveguide array accepts light from a set of sources at the input end and guides the light down each waveguide to an aluminum corner mirror that efficiently deflects light away from the probe axis. Light losses at each stage are small (input coupling loss, 0.4 ± 0.3 dB; bend loss, negligible; propagation loss, 3.1 ± 1 dB/cm using the outscattering method and 3.2 ± 0.4 dB/cm using the cutback method; corner mirror loss, 1.5 ± 0.4 dB); a waveguide coupled, for example, to a 5 mW source will deliver over 1.5 mW to a target at a depth of 1 cm.

Three-Dimensionally Engineered Normal Human Broncho-epithelial Tissue-Like Assemblies: Target Tissues for Human Respiratory Viral Infections

NASA Technical Reports Server (NTRS)

Goodwin, T. J.; McCarthy, M.; Lin, Y-H

2006-01-01

In vitro three-dimensional (3D) human broncho-epithelial (HBE) tissue-like assemblies (3D HBE TLAs) from this point forward referred to as TLAs were engineered in Rotating Wall Vessel (RWV) technology to mimic the characteristics of in vivo tissues thus providing a tool to study human respiratory viruses and host cell interactions. The TLAs were bioengineered onto collagen-coated cyclodextran microcarriers using primary human mesenchymal bronchial-tracheal cells (HBTC) as the foundation matrix and an adult human bronchial epithelial immortalized cell line (BEAS-2B) as the overlying component. The resulting TLAs share significant characteristics with in vivo human respiratory epithelium including polarization, tight junctions, desmosomes, and microvilli. The presence of tissue-like differentiation markers including villin, keratins, and specific lung epithelium markers, as well as the production of tissue mucin, further confirm these TLAs differentiated into tissues functionally similar to in vivo tissues. Increasing virus titers for human respiratory syncytial virus (wtRSVA2) and parainfluenza virus type 3 (wtPIV3 JS) and the detection of membrane bound glycoproteins over time confirm productive infections with both viruses. Therefore, TLAs mimic aspects of the human respiratory epithelium and provide a unique capability to study the interactions of respiratory viruses and their primary target tissue independent of the host's immune system.

Asteroid collisions: Target size effects and resultant velocity distributions

NASA Technical Reports Server (NTRS)

Ryan, Eileen V.

1993-01-01

To study the dynamic fragmentation of rock to simulate asteroid collisions, we use a 2-D, continuum damage numerical hydrocode which models two-body impacts. This hydrocode monitors stress wave propagation and interaction within the target body, and includes a physical model for the formation and growth of cracks in rock. With this algorithm we have successfully reproduced fragment size distributions and mean ejecta speeds from laboratory impact experiments using basalt, and weak and strong mortar as target materials. Using the hydrocode, we have determined that the energy needed to fracture a body has a much stronger dependence on target size than predicted from most scaling theories. In addition, velocity distributions obtained indicate that mean ejecta speeds resulting from large-body collisions do not exceed escape velocities.

Distribution of semduramicin in hen eggs and tissues after administration of cross-contaminated feed.

PubMed

Olejnik, Małgorzata; Szprengier-Juszkiewicz, Teresa; Jedziniak, Piotr

2014-01-01

Semduramicin is an ionophore coccidiostat used in the poultry industry as a feed additive. Cross-contamination of feeds for non-target animals with semduramicin is unavoidable. However, it is not known whether undesirable residues of semduramicin may occur in food after cross-contaminated feed is administered to animals. The aim of the work was to determine the levels of semduramicin in hen eggs (yolks and albumen) and tissues (liver, muscle, spleen, gizzard, ovarian yolks and ovaries) after administration of feed contaminated with 0.27 mg kg(-1) of this coccidiostat. The residues were determined using LC-MS/MS. The distribution pattern confirmed the high lipophilicity of semduramicin. Residues were found mainly in egg yolks (28.8 µg kg(-1)), ovarian yolks (19.5 µg kg(-1)) and liver (2.57 µg kg(-1)), while hens' muscle was free from semduramicin (LOD = 0.1 µg kg(-1)). Among edible tissues, the maximum level (2 µg kg(-1)) was exceeded only in the liver.

Tissue distribution of pretomanid in rat brain via mass spectrometry imaging.

PubMed

Shobo, Adeola; Bratkowska, Dominika; Baijnath, Sooraj; Naiker, Suhashni; Somboro, Anou M; Bester, Linda A; Singh, Sanil D; Naicker, Tricia; Kruger, Hendrik G; Govender, Thavendran

2016-01-01

1. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) combines the sensitivity and selectivity of mass spectrometry with spatial analysis to provide a new dimension for histological analyses of the distribution of drugs in tissue. Pretomanid is a pro-drug belonging to a class of antibiotics known as nitroimidizoles, which have been proven to be active under hypoxic conditions and to the best of our knowledge there have been no studies investigating the distribution and localisation of this class of compounds in the brain using MALDI MSI. 2. Herein, we report on the distribution of pretomanid in the healthy rat brain after intraperitoneal administration (20 mg/kg) using MALDI MSI. Our findings showed that the drug localises in specific compartments of the rat brain viz. the corpus callosum, a dense network of neurons connecting left and right cerebral hemispheres. 3. This study proves that MALDI MSI technique has great potential for mapping the pretomanid distribution in uninfected tissue samples, without the need for molecular labelling.

Pharmacokinetics of warfarin in rats: role of serum protein binding and tissue distribution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cheung, W.K.

The purpose of this study was to explore the role of serum protein binding and tissue distribution in the non-linear pharmacokinetics of warfarin in rats. The first phase of the research was an attempt to elucidate the causes of intersubject differences in serum protein binding of warfarin in rats. It was found that the distribution of S-warfarin between blood and liver, kidneys, muscle, or fatty tissue was non-linear. Based on the tissue distribution data obtained, a physiologically-based pharmacokinetic model was developed to describe the time course of S-warfarin concentrations in the serum and tissues of rats. The proposed model wasmore » able to display the dose-dependent pharmacokinetics of warfarin in rats. Namely a lower clearance and a smaller apparent volume of distribution with increasing dose, which appear to be due to the presence of capacity-limited, high-affinity binding sites for warfarin in various tissues. To determine if the binding of warfarin to the high-affinity binding sites in the liver of rats is reversible, concentrations of S-warfarin in the liver and serum of rats were monitored for a very long time after an intravenous injection of a 1 mg/kg dose. In another study in rats, non-radioactive warfarin was found to be able to displace tissue-bound C/sup 14/-warfarin which was administered about 200 hours before the i.v. injection of the non-radioactive warfarin, showing that the binding of warfarin to the high-affinity binding sites in the body is persistent and reversible.« less

Carbon-14 radiolabeling and tissue distribution evaluation of MMV390048.

PubMed

Sonopo, Molahlehi S; Pillay, Adushan; Chibale, Kelly; Marjanovic-Painter, Biljana; Donini, Cristina; Zeevaart, Jan R

2016-12-01

The antimalarial compound MMV390048 ([ 14 C]-11) was labeled with carbon-14 isotope via a 3-step synthesis. It was obtained in a 15.5% radiochemical overall yield from carbon-14 labeled methyl iodide with a radiochemical purity of >99%. After single oral administration of [ 14 C]-11 to albino and pigmented rats its tissue distribution profile was studied. Tissue distribution results showed high local exposure in the GI tract and excretory organs but low exposure of all other tissues. The radioactivity uptake was higher in the eyes of the pigmented rats than in the eyes of the albino rats at all-time points. The highest accumulation reached in the eyes of the pigmented rats was 0.46% at 6 hours. However, these levels are still very low as compared to the other organs studied. There was very little radioactivity from MMV390048 ([ 14 C]-11) present in the skin of both the albino and pigmented rats. The results obtained are supportive of further development of MMV390048 as a potential antimalarial compound. Copyright © 2016 John Wiley & Sons, Ltd.

Shared target antigens on cancer cells and tissue stem cells: go or no-go for CAR T cells?

PubMed

Hombach, Andreas A; Abken, Hinrich

2017-02-01

Adoptive therapy with chimeric antigen receptor (CAR) T cells redirected towards CD19 produces remissions of B cell malignancies, however, it also eradicates healthy B cells sharing the target antigen. Such 'on-target off-tumor' toxicity raises serious safety concerns when the target antigen is also expressed by tissue stem cells, with the risk of lasting tissue destruction. Areas covered: We discuss CAR T cell targeting of activation antigens versus lineage associated antigens on the basis of recent experimental and animal data and the literature in the field. Expert commentary: Targeting an activation associated antigen which is transiently expressed by stem cells seems to be safe, like CAR T cells targeting CD30 spare CD30 + hematopoietic stem and progenitor cells while eliminating CD30 + lymphoma cells, whereas targeting lineage associated antigens which increase in expression during cell maturation, like folate receptor-β and CD123, is of risk to destruct tissue stem cells.

Predictive analysis of thermal distribution and damage in thermotherapy on biological tissue

NASA Astrophysics Data System (ADS)

Fanjul-Vélez, Félix; Arce-Diego, José Luis

2007-05-01

The use of optical techniques is increasing the possibilities and success of medical praxis in certain cases, either in tissue characterization or treatment. Photodynamic therapy (PDT) or low intensity laser treatment (LILT) are two examples of the latter. Another very interesting implementation is thermotherapy, which consists of controlling temperature increase in a pathological biological tissue. With this method it is possible to provoke an improvement on specific diseases, but a previous analysis of treatment is needed in order for the patient not to suffer any collateral damage, an essential point due to security margins in medical procedures. In this work, a predictive analysis of thermal distribution in a biological tissue irradiated by an optical source is presented. Optical propagation is based on a RTT (Radiation Transport Theory) model solved via a numerical Monte Carlo method, in a multi-layered tissue. Data obtained are included in a bio-heat equation that models heat transference, taking into account conduction, convection, radiation, blood perfusion and vaporization depending on the specific problem. Spatial-temporal differential bio-heat equation is solved via a numerical finite difference approach. Experimental temperature distributions on animal tissue irradiated by laser radiation are shown. From thermal distribution in tissue, thermal damage is studied, based on an Arrhenius analysis, as a way of predicting harmful effects. The complete model can be used for concrete treatment proposals, as a way of predicting treatment effects and consequently decide which optical source parameters are appropriate for the specific disease, mainly wavelength and optical power, with reasonable security margins in the process.

Plasma vs heart tissue concentration in humans - literature data analysis of drugs distribution.

PubMed

Tylutki, Zofia; Polak, Sebastian

2015-03-12

Little is known about the uptake of drugs into the human heart, although it is of great importance nowadays, when science desires to predict tissue level behavior rather than to measure it. Although the drug concentration in cardiac tissue seems a better predictor for physiological and electrophysiological changes than its level in plasma, knowledge of this value is very limited. Tissue to plasma partition coefficients (Kp) come to rescue since they characterize the distribution of a drug among tissues as being one of the input parameters in physiologically based pharmacokinetic (PBPK) models. The article reviews cardiac surgery and forensic medical studies to provide a reference for drug concentrations in human cardiac tissue. Firstly, the focus is on whether a drug penetrates into heart tissue at a therapeutic level; the provided values refer to antibiotics, antifungals and anticancer drugs. Drugs that directly affect cardiomyocyte electrophysiology are another group of interest. Measured levels of amiodarone, digoxin, perhexiline and verapamil in different sites in human cardiac tissue where the compounds might meet ion channels, gives an insight into how these more lipophilic drugs penetrate the heart. Much data are derived from postmortem studies and they provide insight to the cardiac distribution of more than 200 drugs. The analysis depicts potential problems in defining the active concentration location, what may indirectly suggest multiple mechanisms involved in the drug distribution within the heart. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Distributed MIMO Radar for Imaging and High Resolution Target Localization

DTIC Science & Technology

2012-02-02

Reduction in Distributed MIMO Radar with Multi-Carrier OFDM Signals Carl Georgeson 11/23/2010 Approved 17 • 10-019 Algorithms for Target Location and...28-2012 Final Report 04/15/2009 - 11/30/2011 Distributed MIMO Radar for Imaging and High Resolution Target Localization FA9550-09-1-0303 Alexander M...error for the general case of MIMO radar with multiple waveforms with non-coherent and coherent observations; (b) finds a closed-form solution for the

Immunodetection of 11 beta-hydroxysteroid dehydrogenase type 2 in human mineralocorticoid target tissues: evidence for nuclear localization.

PubMed

Shimojo, M; Ricketts, M L; Petrelli, M D; Moradi, P; Johnson, G D; Bradwell, A R; Hewison, M; Howie, A J; Stewart, P M

1997-03-01

11 beta-Hydroxysteroid dehydrogenase (11 beta HSI) is an enzyme complex responsible for the conversion of hormonally active cortisol to inactive cortisone; two isoforms of the enzyme have been cloned and characterized. Clinical observations from patients with the hypertensive syndrome apparent mineralocorticoid excess, recently explained on the basis of mutations in the human 11 beta HSD2 gene, suggest that it is the 11 beta HSD2 isoform that serves a vital role in dictating specificity upon the mineralocorticoid receptor (MR). We have raised a novel antibody in sheep against human 11 beta HSD2 using synthetic multiantigenic peptides and have examined the localization and subcellular distribution of 11 beta HSD2 in mineralocorticoid target tissues. The immunopurified antibody recognized a single band of approximately 44 kDa in placenta, trophoblast, and distal colon. In kidney tissue, two bands of approximately 44 and 48 kDa were consistently observed. No signal was seen in decidua, adrenal, or liver. Immunoperoxidase studies on the mineralocorticoid target tissues, kidney, colon, and parotid gland indicated positive staining in epithelial cells known to express the MR: respectively, renal collecting ducts, surface and crypt colonic epithelial cells, and parotid duct epithelial cells. No staining was seen in these tissues in other sites. The intracellular localization of 11 beta HSD2 in kidney and colon epithelial cells was addressed using confocal laser microscopy. Parallel measurements of 11 beta HSD2 and nuclear propidium iodide fluorescence on sections scanned through an optical section of approximately 0.1 micron indicated significant 11 beta HSD2 immunofluorescence in the nucleus. In human kidney, colon, and salivary gland, 11 beta HSD2 protects the MR from glucocorticoid excess in an autocrine fashion. Furthermore, within these tissues, 11 beta HSD2, which had been considered to be a microsomal enzyme, is also found in the nucleus, suggesting that the

Widespread Non-Hematopoietic Tissue Distribution by Transplanted Human Progenitor Cells with High Aldehyde Dehydrogenase Activity

PubMed Central

Hess, David A.; Craft, Timothy P.; Wirthlin, Louisa; Hohm, Sarah; Zhou, Ping; Eades, William C.; Creer, Michael H.; Sands, Mark S.; Nolta, Jan A.

2011-01-01

Transplanted adult progenitor cells distribute to peripheral organs and can promote endogenous cellular repair in damaged tissues. However, development of cell-based regenerative therapies has been hindered by the lack of pre-clinical models to efficiently assess multiple organ distribution and difficulty defining human cells with regenerative function. After transplantation into beta-glucuronidase (GUSB)-deficient NOD/SCID/MPSVII mice, we characterized the distribution of lineage depleted human umbilical cord blood-derived cells purified by selection using high aldehyde dehydrogenase activity (ALDH) with CD133 co-expression. ALDHhi or ALDHhiCD133+ cells produced robust hematopoietic reconstitution, and variable levels of tissue distribution in multiple organs. GUSB+ donor cells that co-expressed human (HLA-A,B,C) and hematopoietic (CD45+) cell surface markers were the primary cell phenotype found adjacent to the vascular beds of several tissues, including islet and ductal regions of mouse pancreata. In contrast, variable phenotypes were detected in the chimeric liver, with HLA+/CD45+ cells demonstrating robust GUSB expression adjacent to blood vessels, and CD45−/HLA− cells with diluted GUSB expression predominant in the liver parenchyma. However, true non-hematopoietic human (HLA+/CD45−) cells were rarely detected in other peripheral tissues, suggesting that these GUSB+/HLA−/CD45− cells in the liver were a result of downregulated human surface marker expression in vivo, not widespread seeding of non-hematopoietic cells. However, relying solely on continued expression of cell surface markers, as employed in traditional xenotransplantation models, may underestimate true tissue distribution. ALDH-expressing progenitor cells demonstrated widespread and tissue-specific distribution of variable cellular phenotypes, indicating that these adult progenitor cells should be explored in transplantation models of tissue damage. PMID:18055447

New method for generating breast models featuring glandular tissue spatial distribution

NASA Astrophysics Data System (ADS)

Paixão, L.; Oliveira, B. B.; Oliveira, M. A.; Teixeira, M. H. A.; Fonseca, T. C. F.; Nogueira, M. S.

2016-02-01

Mammography is the main radiographic technique used for breast imaging. A major concern with mammographic imaging is the risk of radiation-induced breast cancer due to the high sensitivity of breast tissue. The mean glandular dose (DG) is the dosimetric quantity widely accepted to characterize the risk of radiation induced cancer. Previous studies have concluded that DG depends not only on the breast glandular content but also on the spatial distribution of glandular tissue within the breast. In this work, a new method for generating computational breast models featuring skin composition and glandular tissue distribution from patients undergoing digital mammography is proposed. Such models allow a more accurate way of calculating individualized breast glandular doses taking into consideration the glandular tissue fraction. Sixteen breast models of four patients with different glandularity breasts were simulated and the results were compared with those obtained from recommended DG conversion factors. The results show that the internationally recommended conversion factors may be overestimating the mean glandular dose to less dense breasts and underestimating the mean glandular dose for denser breasts. The methodology described in this work constitutes a powerful tool for breast dosimetry, especially for risk studies.

A lead isotope distribution study in swine tissue using ICP-MS

USGS Publications Warehouse

May, T.W.; Wiedmeyer, Ray H.; Brown, L.D.; Casteel, S.W.

1999-01-01

In the United States lead is an ubiquitous environmental pollutant that is a serious human health hazard, especially for women of childbearing age, developing fetuses, and young children. Information concerning the uptake and distribution of lead to maternal and fetal tissues during pregnancy is poorly documented. A study was designed using domestic swine and lead isotope enrichment methodology to focus on maternal absorption and distribution of lead into bone and soft tissues, including the fetal compartment, under varying conditions of oral lead exposure and during altered physiological states (pregnant vs unbred). Total lead levels and Pb207/Pb206 ratios in bone (femur and vertebra), blood, and soft tissues (liver, kidney, brain) were determined by ICP-MS. Lead in fetal tissues derived from maternal bone could be differentiated from that derived from exogenous dosing. Unbred swine absorbed much less lead than pregnant females receiving the same dose. The accuracy and precision of ICP-MS at the instrumental level and for the entire method (sample collection, digestion, and analysis) were evaluated for both Pb207/Pb206 ratios and total lead. Several changes were suggested in method design to improve both instrumental and total method precision.

The effect of uterine motion and uterine margins on target and normal tissue doses in intensity modulated radiation therapy of cervical cancer

NASA Astrophysics Data System (ADS)

Gordon, J. J.; Weiss, E.; Abayomi, O. K.; Siebers, J. V.; Dogan, N.

2011-05-01

In intensity modulated radiation therapy (IMRT) of cervical cancer, uterine motion can be larger than cervix motion, requiring a larger clinical target volume to planning target volume (CTV-to-PTV) margin around the uterine fundus. This work simulates different motion models and margins to estimate the dosimetric consequences. A virtual study used image sets from ten patients. Plans were created with uniform margins of 1 cm (PTVA) and 2.4 cm (PTVC), and a margin tapering from 2.4 cm at the fundus to 1 cm at the cervix (PTVB). Three inter-fraction motion models (MM) were simulated. In MM1, all structures moved with normally distributed rigid body translations. In MM2, CTV motion was progressively magnified as one moved superiorly from the cervix to the fundus. In MM3, both CTV and normal tissue motion were magnified as in MM2, modeling the scenario where normal tissues move into the void left by the mobile uterus. Plans were evaluated using static and percentile DVHs. For a conventional margin (PTVA), quasi-realistic uterine motion (MM3) reduces fundus dose by about 5 Gy and increases normal tissue volumes receiving 30-50 Gy by ~5%. A tapered CTV-to-PTV margin can restore fundus and CTV doses, but will increase normal tissue volumes receiving 30-50 Gy by a further ~5%.

LASER BIOLOGY: Visualisation of the distributions of melanin and indocyanine green in biological tissues

NASA Astrophysics Data System (ADS)

Genina, E. A.; Fedosov, I. V.; Bashkatov, A. N.; Zimnyakov, D. A.; Altshuler, G. B.; Tuchin, V. V.

2008-03-01

A double-wavelength laser scanning microphotometer with the high spectral and spatial resolutions is developed for studying the distribution of endogenic and exogenic dyes in biological tissues. Samples of hair and skin biopsy with hair follicles stained with indocyanine green are studied. The spatial distribution of indocyanine green and melanin in the biological tissue is determined from the measured optical transmittance.

In vivo tissue distribution and efficacy studies for cyclosporin A loaded nano-decorated subconjunctival implants.

PubMed

Yavuz, Burçin; Bozdağ Pehlivan, Sibel; Kaffashi, Abbas; Çalamak, Semih; Ulubayram, Kezban; Palaska, Erhan; Çakmak, Hasan Basri; Ünlü, Nurşen

2016-11-01

Biodegradable implants are promising drug delivery systems for sustained release ocular drug delivery with the benefits such as minimum systemic side effects, constant drug concentration at the target site and getting cleared without surgical removal. Dry eye syndrome (DES) is a common disease characterized with the changes in ocular epithelia surface and results in inflammatory reaction that might lead to blindness. Cyclosporin A (CsA) is a cyclic peptide that is frequently employed for the treatment of DES and it needs to be applied several times a day in tear drops form. The aim of this study was to evaluate in vivo behavior and efficacy of the developed nano-decorated subconjunctival implant systems for sustained release CsA delivery. Biodegradable Poly-ɛ-caprolactone (PCL) implant or micro-fiber implants containing CsA loaded poly-lactide-co-glycolide (85:15) (PLGA) or PCL nanoparticles were prepared in order to achieve sustained release. Two of the formulations PCL-PLGA-NP-F and PCL-PCL-NP-I were selected for in vivo evaluation based on their in vitro characteristics determined in our previous study. In this study, formulations were implanted to Swiss Albino mice with induced dry eye syndrome to investigate the ocular distribution of CsA following subconjunctival implantation and to evaluate the efficacy. Tissue distribution study indicated that CsA was present in ocular tissues such as cornea, sclera and lens even 90 days after the application and blood CsA levels were found lower than ocular tissues. Efficacy studies also showed that application of CsA-loaded fiber implant formulation resulted in faster recovery based on their staining scores.

Intravenous Exposure of Pregnant Mice to Silver Nanoparticles: Silver Tissue Distribution and Effects in Maternal and Extra-Embryonic Tissues and Embryos

NASA Astrophysics Data System (ADS)

Austin, Carlye Anne

This research explores the tissue distribution of silver, as well as adverse effects in pregnant mice and embryos, following prenatal silver nanoparticle (AgNP) exposure. Chapter one of this dissertation is a survey of the published literature on the reproductive and/or developmental toxicity of AgNPs. The available data indicate that AgNPs adversely affect sperm count, viability, and/or motility both in vivo and in vitro, and cause apoptosis and necrosis in spermatogonial stem cells and testicular cells. Additionally, AgNP exposure results in mortality and morphological deformities in fish embryos, but produces no adverse effects in chicken embryos. The current published research on in vivo AgNP exposure to mammals during gestation consists of only three studies, one of which is described in chapter two of this dissertation. These studies report results that may suggest a potential for adverse effects on fetal development (e.g. , decreased viability and fetal and placental weights, increased incidence of developmentally young embryos), but additional research is needed. Chapter two of this dissertation investigates the distribution of silver in tissues of pregnant mice and gestation day (GD) 10 embryos following intravenous maternal exposure to 50 nm AgNPs during early organogenesis (GDs 7-9). Examinations of embryo morphology and histology were also performed. Results demonstrated the presence of silver in all organs and tissues examined. Silver concentrations were highest in liver, spleen, and visceral yolk sac, and lowest in embryos. Groups of mice were also treated with soluble silver nitrate, and the pattern of silver tissue distribution following silver nitrate exposure was similar to that which followed AgNP treatment. Transmission electron microscopy-energy dispersive x-ray spectroscopy (TEM-EDS) confirmed the presence of vesicle-bound nanoparticulate silver in visceral yolk sac endoderm, but not mesoderm. This finding, along with the high silver

In Vivo Bio-distribution and Efficient Tumor Targeting of Gelatin/Silica Nanoparticles for Gene Delivery

NASA Astrophysics Data System (ADS)

Zhao, Xueqin; Wang, Jun; Tao, SiJie; Ye, Ting; Kong, Xiangdong; Ren, Lei

2016-04-01

The non-viral gene delivery system is an attractive alternative to cancer therapy. The clinical success of non-viral gene delivery is hampered by transfection efficiency and tumor targeting, which can be individually overcome by addition of functional modules such as cell penetration or targeting. Here, we first engineered the multifunctional gelatin/silica (GS) nanovectors with separately controllable modules, including tumor-targeting aptamer AGRO100, membrane-destabilizing peptide HA2, and polyethylene glycol (PEG), and then studied their bio-distribution and in vivo transfection efficiencies by contrast resonance imaging (CRI). The results suggest that the sizes and zeta potentials of multifunctional gelatin/silica nanovectors were 203-217 nm and 2-8 mV, respectively. Functional GS-PEG nanoparticles mainly accumulated in the liver and tumor, with the lowest uptake by the heart and brain. Moreover, the synergistic effects of tumor-targeting aptamer AGRO100 and fusogenic peptide HA2 promoted the efficient cellular internalization in the tumor site. More importantly, the combined use of AGRO100 and PEG enhanced tumor gene expression specificity and effectively reduced toxicity in reticuloendothelial system (RES) organs after intravenous injection. Additionally, low accumulation of GS-PEG was observed in the heart tissues with high gene expression levels, which could provide opportunities for non-invasive gene therapy.

Tissue distribution of sup 3 H-nicotine in rats after bolus or constant injection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chowdhury, P.; Pasley, J.N.; Rayford, P.L.

1989-01-01

Two groups of rats, (N = 7), were fasted for 24 hrs prior to the study. On the day of the experiment, the animals were anesthetized and infused with either 5 ml nicotine solution (200 {mu}g/L) in saline containing 5 {mu}c {sup 3}H-nicotine, (sp. activity 50-80 mCi/mol) for 90 minutes or injected as a bolus with 0.5 ml of the same nicotine (200 {mu}g/L) solution. The animals were sacrificed 60 minutes after the injection or after the infusion was stopped. Blood and tissue samples were counted by liquid scintillation counting. Percent distribution of {sup 3}H-nicotine per gm of tissue wasmore » calculated from the total radioactivity recovered in individual tissues over the total activity injected into the rat and the values were compared using student's t test. Results: Distribution of {sup 3}H-nicotine was found highest in kidney (45-49%) among all tissues examined and was not different between routes of administration. Significantly higher retention of {sup 3}H-nicotine was found with continuous infusion in esophagus, fundus, antrum, spleen, cecum, pancreas, testes, heart and muscle when {sup 3}H-nicotine retentions were compared with bolus injection. In contrast, the distribution of {sup 3}H-nicotine in adrenal gland, was significantly lower in continuous infusion group. Distribution in blood was 6 fold higher in continuous infusion (7.26%) compared to bolus (1.11%) injection. The distribution {sup 3}H-nicotine in other tissues were not different by either routes of injection.« less

Bioaccumulation and tissue distribution of antibiotics in wild marine fish from Laizhou Bay, North China.

PubMed

Liu, Sisi; Bekele, Tadiyose-Girma; Zhao, Hongxia; Cai, Xiyun; Chen, Jingwen

2018-08-01

Information about bioaccumulation and tissue distribution of antibiotics in wild marine fish is still limited. In the present study, tissue levels, bioaccumulation and distribution patterns of 9 sulfonamide (SA), trimethoprim (TMP), 5 fluoroquinolone (FQ), and 4 macrolide (ML) antibiotics were investigated in gill, muscle, kidney, and liver tissues of seven wild fish species collected from Laizhou Bay, North China in 2016. All the 19 antibiotics were detected in these fish tissues with the total concentrations ranging from 22ng/g dry weight (dw) to 500ng/g dw. The mean values of logarithm bioaccumulation factors (BAFs) in the gills, muscles, kidneys, and livers ranged from 2.2 to 4.8, 1.9 to 4.0, 2.5 to 4.9, and 2.5 to 5.4, respectively. Log BAFs of antibiotics in these tissues significantly increased (r=0.61-0.77, p<0.001) with their logarithm values of liposome-water distribution coefficient (D lipw ) except in the muscles, suggesting that D lipw can well assess the bioaccumulation potentials of antibiotics in phospholipid-rich tissues. In general, the SAs, TMP, and FQs were primarily accumulated in the muscles and the MLs were primarily in the livers, which may be related to their toxicokinetic processes of these marine fish. The present study for the first time reported the tissue distribution patterns of antibiotics in wild marine fish. Copyright © 2018 Elsevier B.V. All rights reserved.

Multiple functionalized carbon quantum dots for targeting glioma and tissue imaging

NASA Astrophysics Data System (ADS)

Gao, Lipeng; Zhao, Xiao; Wang, Jing; Wang, Yiting; Yu, Lei; Peng, Hui; Zhu, Jianzhong

2018-01-01

Carbon quantum dots (CQDs) was successfully functionalized with Mal-PEG-NHS linked RGERPPR. They exhibit double functions of both tissue imaging and targeting to brain gliomas. The mean size of the functionalized CQDs about 9.0 ± 2.0 nm. The maximum absorption wavelength of the functionalized CQDs appear at 230 nm. The peak of the fluorescence spectra for the functionalized CQDs is at 460 nm, red shifted by 20 nm comparing with the unmodified CQDs. This may be due to the increased particle size. The functionalized CQDs were successfully applied to imaging and targeting gliomas.

A Method for Medical Diagnosis Based on Optical Fluence Rate Distribution at Tissue Surface

PubMed Central

Hamdy, Omnia; El-Azab, Jala; Al-Saeed, Tarek A.; Hassan, Mahmoud F.

2017-01-01

Optical differentiation is a promising tool in biomedical diagnosis mainly because of its safety. The optical parameters’ values of biological tissues differ according to the histopathology of the tissue and hence could be used for differentiation. The optical fluence rate distribution on tissue boundaries depends on the optical parameters. So, providing image displays of such distributions can provide a visual means of biomedical diagnosis. In this work, an experimental setup was implemented to measure the spatially-resolved steady state diffuse reflectance and transmittance of native and coagulated chicken liver and native and boiled breast chicken skin at 635 and 808 nm wavelengths laser irradiation. With the measured values, the optical parameters of the samples were calculated in vitro using a combination of modified Kubelka-Munk model and Bouguer-Beer-Lambert law. The estimated optical parameters values were substituted in the diffusion equation to simulate the fluence rate at the tissue surface using the finite element method. Results were verified with Monte-Carlo simulation. The results obtained showed that the diffuse reflectance curves and fluence rate distribution images can provide discrimination tools between different tissue types and hence can be used for biomedical diagnosis. PMID:28930158

A Method for Medical Diagnosis Based on Optical Fluence Rate Distribution at Tissue Surface.

PubMed

Hamdy, Omnia; El-Azab, Jala; Al-Saeed, Tarek A; Hassan, Mahmoud F; Solouma, Nahed H

2017-09-20

Optical differentiation is a promising tool in biomedical diagnosis mainly because of its safety. The optical parameters' values of biological tissues differ according to the histopathology of the tissue and hence could be used for differentiation. The optical fluence rate distribution on tissue boundaries depends on the optical parameters. So, providing image displays of such distributions can provide a visual means of biomedical diagnosis. In this work, an experimental setup was implemented to measure the spatially-resolved steady state diffuse reflectance and transmittance of native and coagulated chicken liver and native and boiled breast chicken skin at 635 and 808 nm wavelengths laser irradiation. With the measured values, the optical parameters of the samples were calculated in vitro using a combination of modified Kubelka-Munk model and Bouguer-Beer-Lambert law. The estimated optical parameters values were substituted in the diffusion equation to simulate the fluence rate at the tissue surface using the finite element method. Results were verified with Monte-Carlo simulation. The results obtained showed that the diffuse reflectance curves and fluence rate distribution images can provide discrimination tools between different tissue types and hence can be used for biomedical diagnosis.

A hybrid approach to advancing quantitative prediction of tissue distribution of basic drugs in human

DOE Office of Scientific and Technical Information (OSTI.GOV)

Poulin, Patrick, E-mail: patrick-poulin@videotron.ca; Ekins, Sean; Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, MD 21201

A general toxicity of basic drugs is related to phospholipidosis in tissues. Therefore, it is essential to predict the tissue distribution of basic drugs to facilitate an initial estimate of that toxicity. The objective of the present study was to further assess the original prediction method that consisted of using the binding to red blood cells measured in vitro for the unbound drug (RBCu) as a surrogate for tissue distribution, by correlating it to unbound tissue:plasma partition coefficients (Kpu) of several tissues, and finally to predict volume of distribution at steady-state (V{sub ss}) in humans under in vivo conditions. Thismore » correlation method demonstrated inaccurate predictions of V{sub ss} for particular basic drugs that did not follow the original correlation principle. Therefore, the novelty of this study is to provide clarity on the actual hypotheses to identify i) the impact of pharmacological mode of action on the generic correlation of RBCu-Kpu, ii) additional mechanisms of tissue distribution for the outlier drugs, iii) molecular features and properties that differentiate compounds as outliers in the original correlation analysis in order to facilitate its applicability domain alongside the properties already used so far, and finally iv) to present a novel and refined correlation method that is superior to what has been previously published for the prediction of human V{sub ss} of basic drugs. Applying a refined correlation method after identifying outliers would facilitate the prediction of more accurate distribution parameters as key inputs used in physiologically based pharmacokinetic (PBPK) and phospholipidosis models.« less

Temperature distribution analysis of tissue water vaporization during microwave ablation: experiments and simulations.

PubMed

Ai, Haiming; Wu, Shuicai; Gao, Hongjian; Zhao, Lei; Yang, Chunlan; Zeng, Yi

2012-01-01

The temperature distribution in the region near a microwave antenna is a critical factor that affects the entire temperature field during microwave ablation of tissue. It is challenging to predict this distribution precisely, because the temperature in the near-antenna region varies greatly. The effects of water vaporisation and subsequent tissue carbonisation in an ex vivo porcine liver were therefore studied experimentally and in simulations. The enthalpy and high-temperature specific absorption rate (SAR) of liver tissues were calculated and incorporated into the simulation process. The accuracy of predictions for near-field temperatures in our simulations has reached the level where the average maximum error is less than 5°C. In addition, a modified thermal model that accounts for water vaporisation and the change in the SAR distribution pattern is proposed and validated with experiment. The results from this study may be useful in the clinical practice of microwave ablation and can be applied to predict the temperature field in surgical planning.

Biomimetic proteolipid vesicles for targeting inflamed tissues

NASA Astrophysics Data System (ADS)

Molinaro, R.; Corbo, C.; Martinez, J. O.; Taraballi, F.; Evangelopoulos, M.; Minardi, S.; Yazdi, I. K.; Zhao, P.; De Rosa, E.; Sherman, M. B.; de Vita, A.; Toledano Furman, N. E.; Wang, X.; Parodi, A.; Tasciotti, E.

2016-09-01

A multitude of micro- and nanoparticles have been developed to improve the delivery of systemically administered pharmaceuticals, which are subject to a number of biological barriers that limit their optimal biodistribution. Bioinspired drug-delivery carriers formulated by bottom-up or top-down strategies have emerged as an alternative approach to evade the mononuclear phagocytic system and facilitate transport across the endothelial vessel wall. Here, we describe a method that leverages the advantages of bottom-up and top-down strategies to incorporate proteins derived from the leukocyte plasma membrane into lipid nanoparticles. The resulting proteolipid vesicles--which we refer to as leukosomes--retained the versatility and physicochemical properties typical of liposomal formulations, preferentially targeted inflamed vasculature, enabled the selective and effective delivery of dexamethasone to inflamed tissues, and reduced phlogosis in a localized model of inflammation.

Laser induced heat source distribution in bio-tissues

NASA Astrophysics Data System (ADS)

Li, Xiaoxia; Fan, Shifu; Zhao, Youquan

2006-09-01

During numerical simulation of laser and tissue thermal interaction, the light fluence rate distribution should be formularized and constituted to the source term in the heat transfer equation. Usually the solution of light irradiative transport equation is given in extreme conditions such as full absorption (Lambert-Beer Law), full scattering (Lubelka-Munk theory), most scattering (Diffusion Approximation) et al. But in specific conditions, these solutions will induce different errors. The usually used Monte Carlo simulation (MCS) is more universal and exact but has difficulty to deal with dynamic parameter and fast simulation. Its area partition pattern has limits when applying FEM (finite element method) to solve the bio-heat transfer partial differential coefficient equation. Laser heat source plots of above methods showed much difference with MCS. In order to solve this problem, through analyzing different optical actions such as reflection, scattering and absorption on the laser induced heat generation in bio-tissue, a new attempt was made out which combined the modified beam broaden model and the diffusion approximation model. First the scattering coefficient was replaced by reduced scattering coefficient in the beam broaden model, which is more reasonable when scattering was treated as anisotropic scattering. Secondly the attenuation coefficient was replaced by effective attenuation coefficient in scattering dominating turbid bio-tissue. The computation results of the modified method were compared with Monte Carlo simulation and showed the model provided reasonable predictions of heat source term distribution than past methods. Such a research is useful for explaining the physical characteristics of heat source in the heat transfer equation, establishing effective photo-thermal model, and providing theory contrast for related laser medicine experiments.

[Rare earth elements contents and distribution characteristics in nasopharyngeal carcinoma tissue].

PubMed

Zhang, Xiangmin; Lan, Xiaolin; Zhang, Lingzhen; Xiao, Fufu; Zhong, Zhaoming; Ye, Guilin; Li, Zong; Li, Shaojin

2016-03-01

To investigate the rare earth elements(REEs) contents and distribution characteristics in nasopharyngeal carcinoma( NPC) tissue in Gannan region. Thirty patients of NPC in Gannan region were included in this study. The REEs contents were measured by tandem mass spectrometer inductively coupled plasma(ICP-MS/MS) in 30 patients, and the REEs contents and distribution were analyzed. The average standard deviation value of REEs in lung cancer and normal lung tissues was the minimum mostly. Light REEs content was higher than the medium REEs, and medium REEs content was higher than the heavy REEs content. REEs contents changes in nasopharyngeal carcinoma were variable obviously, the absolute value of Nd, Ce, Pr, Gd and other light rare earth elements were variable widely. The degree of changes on Yb, Tb, Ho and other heavy rare earth elements were variable widely, and there was presence of Eu, Ce negative anomaly(δEu=0. 385 5, δCe= 0. 523 4). The distribution characteristic of REEs contents in NPC patients is consistent with the parity distribution. With increasing atomic sequence, the content is decline wavy. Their distribution patterns were a lack of heavy REEs and enrichment of light REEs, and there was Eu , Ce negative anomaly.

Cooperative tumour cell membrane targeted phototherapy

NASA Astrophysics Data System (ADS)

Kim, Heegon; Lee, Junsung; Oh, Chanhee; Park, Ji-Ho

2017-06-01

The targeted delivery of therapeutics using antibodies or nanomaterials has improved the precision and safety of cancer therapy. However, the paucity and heterogeneity of identified molecular targets within tumours have resulted in poor and uneven distribution of targeted agents, thus compromising treatment outcomes. Here, we construct a cooperative targeting system in which synthetic and biological nanocomponents participate together in the tumour cell membrane-selective localization of synthetic receptor-lipid conjugates (SR-lipids) to amplify the subsequent targeting of therapeutics. The SR-lipids are first delivered selectively to tumour cell membranes in the perivascular region using fusogenic liposomes. By hitchhiking with extracellular vesicles secreted by the cells, the SR-lipids are transferred to neighbouring cells and further spread throughout the tumour tissues where the molecular targets are limited. We show that this tumour cell membrane-targeted delivery of SR-lipids leads to uniform distribution and enhanced phototherapeutic efficacy of the targeted photosensitizer.

Cosmic ray heavy ion LET mapping for aluminum, silicon, and tissue targets

NASA Technical Reports Server (NTRS)

Stassinopoulos, E. G.; Barth, J. M.; Jordan, T. M.

1987-01-01

Linear energy transfer (LET) values in aluminum, silicon, and tissue targets have been calculated for 31 galactic cosmic ray ion species in eight different units. The values are described for single event upset (SEU) effect assessments or radiobiological evaluations. The data are presented in graphical and tabular form.

A Sympathetic Neuron Autonomous Role for Egr3-Mediated Gene Regulation in Dendrite Morphogenesis and Target Tissue Innervation

PubMed Central

Quach, David H.; Oliveira-Fernandes, Michelle; Gruner, Katherine A.; Tourtellotte, Warren G.

2013-01-01

Egr3 is a nerve growth factor (NGF)-induced transcriptional regulator that is essential for normal sympathetic nervous system development. Mice lacking Egr3 in the germline have sympathetic target tissue innervation abnormalities and physiologic sympathetic dysfunction similar to humans with dysautonomia. However, since Egr3 is widely expressed and has pleiotropic function, it has not been clear whether it has a role within sympathetic neurons and if so, what target genes it regulates to facilitate target tissue innervation. Here, we show that Egr3 expression within sympathetic neurons is required for their normal innervation since isolated sympathetic neurons lacking Egr3 have neurite outgrowth abnormalities when treated with NGF and mice with sympathetic neuron-restricted Egr3 ablation have target tissue innervation abnormalities similar to mice lacking Egr3 in all tissues. Microarray analysis performed on sympathetic neurons identified many target genes deregulated in the absence of Egr3, with some of the most significantly deregulated genes having roles in axonogenesis, dendritogenesis, and axon guidance. Using a novel genetic technique to visualize axons and dendrites in a subpopulation of randomly labeled sympathetic neurons, we found that Egr3 has an essential role in regulating sympathetic neuron dendrite morphology and terminal axon branching, but not in regulating sympathetic axon guidance to their targets. Together, these results indicate that Egr3 has a sympathetic neuron autonomous role in sympathetic nervous system development that involves modulating downstream target genes affecting the outgrowth and branching of sympathetic neuron dendrites and axons. PMID:23467373

Estimation of the minimum permeability coefficient in rats for perfusion-limited tissue distribution in whole-body physiologically-based pharmacokinetics.

PubMed

Jeong, Yoo-Seong; Yim, Chang-Soon; Ryu, Heon-Min; Noh, Chi-Kyoung; Song, Yoo-Kyung; Chung, Suk-Jae

2017-06-01

The objective of the current study was to determine the minimum permeability coefficient, P, needed for perfusion-limited distribution in PBPK. Two expanded kinetic models, containing both permeability and perfusion terms for the rate of tissue distribution, were considered: The resulting equations could be simplified to perfusion-limited distribution depending on tissue permeability. Integration plot analyses were carried out with theophylline in 11 typical tissues to determine their apparent distributional clearances and the model-dependent permeabilities of the tissues. Effective surface areas were calculated for 11 tissues from the tissue permeabilities of theophylline and its PAMPA P. Tissue permeabilities of other drugs were then estimated from their PAMPA P and the effective surface area of the tissues. The differences between the observed and predicted concentrations, as expressed by the sum of squared log differences with the present models were at least comparable to or less than the values obtained using the traditional perfusion-limited distribution model for 24 compounds with diverse PAMPA P values. These observations suggest that the use of a combination of the proposed models, PAMPA P and the effective surface area can be used to reasonably predict the pharmacokinetics of 22 out of 24 model compounds, and is potentially applicable to calculating the kinetics for other drugs. Assuming that the fractional distribution parameter of 80% of the perfusion rate is a reasonable threshold for perfusion-limited distribution in PBPK, our theoretical prediction indicates that the pharmacokinetics of drugs having an apparent PAMPA P of 1×10 -6 cm/s or more will follow the traditional perfusion-limited distribution in PBPK for major tissues in the body. Copyright © 2017 Elsevier B.V. All rights reserved.

Hyperspectral target detection using heavy-tailed distributions

NASA Astrophysics Data System (ADS)

Willis, Chris J.

2009-09-01

One promising approach to target detection in hyperspectral imagery exploits a statistical mixture model to represent scene content at a pixel level. The process then goes on to look for pixels which are rare, when judged against the model, and marks them as anomalies. It is assumed that military targets will themselves be rare and therefore likely to be detected amongst these anomalies. For the typical assumption of multivariate Gaussianity for the mixture components, the presence of the anomalous pixels within the training data will have a deleterious effect on the quality of the model. In particular, the derivation process itself is adversely affected by the attempt to accommodate the anomalies within the mixture components. This will bias the statistics of at least some of the components away from their true values and towards the anomalies. In many cases this will result in a reduction in the detection performance and an increased false alarm rate. This paper considers the use of heavy-tailed statistical distributions within the mixture model. Such distributions are better able to account for anomalies in the training data within the tails of their distributions, and the balance of the pixels within their central masses. This means that an improved model of the majority of the pixels in the scene may be produced, ultimately leading to a better anomaly detection result. The anomaly detection techniques are examined using both synthetic data and hyperspectral imagery with injected anomalous pixels. A range of results is presented for the baseline Gaussian mixture model and for models accommodating heavy-tailed distributions, for different parameterizations of the algorithms. These include scene understanding results, anomalous pixel maps at given significance levels and Receiver Operating Characteristic curves.

Measuring tissue oxygenation

NASA Technical Reports Server (NTRS)

Soyemi, Olusola O. (Inventor); Soller, Babs R. (Inventor); Yang, Ye (Inventor)

2009-01-01

Methods and systems for calculating tissue oxygenation, e.g., oxygen saturation, in a target tissue are disclosed. In some embodiments, the methods include: (a) directing incident radiation to a target tissue and determining reflectance spectra of the target tissue by measuring intensities of reflected radiation from the target tissue at a plurality of radiation wavelengths; (b) correcting the measured intensities of the reflectance spectra to reduce contributions thereto from skin and fat layers through which the incident radiation propagates; (c) determining oxygen saturation in the target tissue based on the corrected reflectance spectra; and (d) outputting the determined value of oxygen saturation.

The role of the extracellular matrix in tissue distribution of macromolecules in normal and pathological tissues: potential therapeutic consequences.

PubMed

Wiig, Helge; Gyenge, Christina; Iversen, Per Ole; Gullberg, Donald; Tenstad, Olav

2008-05-01

The interstitial space is a dynamic microenvironment that consists of interstitial fluid and structural molecules of the extracellular matrix, such as glycosaminoglycans (hyaluronan and proteoglycans) and collagen. Macromolecules can distribute in the interstitium only in those spaces unoccupied by structural components, a phenomenon called interstitial exclusion. The exclusion phenomenon has direct consequences for plasma volume regulation. Early studies have assigned a major role to collagen as an excluding agent that accounts for the sterical (geometrical) exclusion. More recently, it has been shown that the contribution of negatively charged glycosaminoglycans might also be significant, resulting in an additional electrostatical exclusion effect. This charge effect may be of importance for drug uptake and suggests that either the glycosaminoglycans or the net charge of macromolecular substances to be delivered may be targeted to increase the available volume and uptake of macromolecular therapeutic agents in tumor tissue. Here, we provide an overview of the structural components of the interstitium and discuss the importance the sterical and electrostatical components have on the dynamics of transcapillary fluid exchange.

[Postmortem distribution of tetrodotoxin in tissues and body fluids of guinea pigs].

PubMed

Liu, Wei; Da, Qing; Shen, Min

2012-06-01

To investigate the postmortem distribution of tetrodotoxin in tissues and body fluids of guinea pig, and to provide method and evidence for forensic identification and clinical diagnosis and treatment. Guinea pigs were intragastric administrated with 100, 50, 15 microg/kg tetrodotoxin, respectively. The poisoning symptoms were observed. The samples of heart, liver, spleen, lung, kidney, brain, stomach, intestines, bile, heart blood and urine were collected. The concentrations of tetrodotoxin in tissues and body fluids were measured with liquid chromatography-tandem mass spectrometry (LC-MS/MS). After administrated with tetrodotoxin, all guinea pigs came out poisoning signs including tachypnea, weary and dead finally. Tetrodotoxin concentrations in lung, stomach, intestines and urine were higher, followed by blood, heart and brain. The concentration in bile was the lowest. Postmortem distribution of tetrodotoxin in guinea pig is uneven. The concentration in the lung, stomach, intestines, urine and heart blood are higher, those tissues could be used for diagnosis of tetrodotoxin poisoning.

Targeted delivery using peptide-functionalised gold nanoparticles to white adipose tissues of obese rats

NASA Astrophysics Data System (ADS)

Thovhogi, Ntevheleni; Sibuyi, Nicole; Meyer, Mervin; Onani, Martin; Madiehe, Abram

2015-02-01

Obesity is a complex metabolic disease of excessive fat accumulation. It is a worldwide epidemic affecting billions of people. Current pharmacological treatment of obesity remains limited and ineffective due to systemic drug toxicity and undesirable side effects. The current epidemic raises a serious need for development of safer drugs to treat obesity. Nanotechnology-based drug delivery system for administering pharmaceutical compound to achieve therapeutic effects is currently an exciting field in cancer treatment. Drug delivery involves either modification of drug release profile, absorption, distribution and/or elimination, for the benefit of improving drug efficacy and safety. Therefore, nanotechnology holds promise in the treatment of diseases including obesity. Gold nanoparticles (GNPs) functionalised with different biomolecules have been successfully used as drug delivery, labelling and imaging tools in biomedical research. In this study, the binding-specificity and targeting ability of adipose homing peptide (AHP)-functionalised GNPs (AHP-GNPs) were evaluated using flow cytometry and inductively coupled plasma-optical emission spectroscopy. Caco-2 cells and rats fed either chow or a high-fat diet were treated with either unfunctionalised GNPs or AHP-GNPs. Cellular uptake of GNPs was detected in cells treated with AHP-GNPs and not those treated with GNPs alone. Binding of AHP to cells was both temperature- and concentration-dependent. Compared to rats treated with GNPs alone, treatment of obese rats with AHP-GNPs resulted in the targeted delivery of the GNPs to the white adipose tissue (WAT). This paper reports the successful targeting of AHP-functionalised GNPs to WAT of obese rats.

Fourier polarimetry of the birefringence distribution of myocardium tissue

NASA Astrophysics Data System (ADS)

Ushenko, O. G.; Dubolazov, O. V.; Ushenko, V. O.; Gorsky, M. P.; Soltys, I. V.; Olar, O. V.

2015-11-01

The results of optical modeling of biological tissues polycrystalline multilayer networks have been presented. Algorithms of reconstruction of parameter distributions were determined that describe the linear and circular birefringence. For the separation of the manifestations of these mechanisms we propose a method of space-frequency filtering. Criteria for differentiation of causes of death due to coronary heart disease (CHD) and acute coronary insufficiency (ACI) were found.

Visceral adipose tissue macrophage-targeted TACE silencing to treat obesity-induced type 2 diabetes.

PubMed

Yong, Seok-Beom; Song, Yoonsung; Kim, Yong-Hee

2017-12-01

Obesity is an increasingly prevalent global health problem. Due to its close relations with metabolic diseases and cancer, new therapeutic approaches for treating obesity and obesity-induced metabolic diseases are required. Visceral white adipose tissue (WAT) has been closely associated with obesity-induced inflammation and adipose tissue macrophages (ATMs) are responsible for obesity-induced inflammation by releasing inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6. TNF-α converting enzyme (TACE) is a transmembrane enzyme that induces the enzymatic cleavage and release of inflammatory cytokines. In this study, we developed a nonviral gene delivery system consisting of an oligopeptide (ATS-9R) that can selectively target visceral ATMs. In here we shows visceral adipose tissue-dominant inflammatory gene over-expressions in obese mouse and our strategy enabled the preferential delivery of therapeutic genes to visceral ATMs and successfully achieved ATM-targeted gene silencing. Finally, ATS-9R-mediated TACE gene silencing in visceral ATMs alleviated visceral fat inflammation and improved type 2 diabetes by reducing whole body inflammation. Copyright © 2017 Elsevier Ltd. All rights reserved.

SU-E-I-44: Some Preliminary Analysis of Angular Distribution of X-Ray Scattered On Soft Tissues

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ganezer, K; Krmar, M; Cvejic, Z

2015-06-15

Purpose: The angular distribution of x-radiation scattered at small angles (up to 16 degrees) from several different animal soft tissue (skin, fat, muscle, retina, etc) were measured using standard equipment devoted to study of crystal structure which provides excellent geometry conditions of measurements. showed measurable differences for different tissues. In the simplest possible case when measured samples do not differ in structure (different concentration solutions) it can be seen that intensity of scattered radiation is decreasing function of the concentration and the peak of the maximum of scattering distribution depends on the concentration as well. Methods: An x-ray scattering profilemore » usually consists of sharp diffraction peak; however some properties of the spatial profiles of scattered radiation as intensity, the peak position, height, area, FWHM, the ratio of peak heights, etc. Results: The data contained measurable differences for different tissues. In the simplest possible case when measured samples do not differ in structure (different concentration solutions) it can be seen that intensity of scattered radiation is decreasing function of the concentration and the peak of the maximum of scattering distribution depends on the concentration as well. Measurements of different samples in the very preliminary phase showed that simple biological material used in study showed slightly different scattering pattern, especially at higher angles (around 10degrees). Intensity of radiation scattered from same tissue type is very dependent on water content and several more parameters. Conclusion: This preliminary study using animal soft tissues on the angular distributions of scattered x-rays suggests that angular distributions of X-rays scattered off of soft tissues might be useful in distinguishing healthy tissue from malignant soft tissue.« less

Radiation induced COX-2 expression and mutagenesis at non-targeted lung tissues of gpt delta transgenic mice

PubMed Central

Chai, Y; Calaf, G M; Zhou, H; Ghandhi, S A; Elliston, C D; Wen, G; Nohmi, T; Amundson, S A; Hei, T K

2013-01-01

Background: Although radiation-induced bystander effects have been confirmed using a variety of endpoints, the mechanism(s) underlying these effects are not well understood, especially for in vivo study. Methods: A 1-cm2 area (1 cm × 1 cm) in the lower abdominal region of gpt delta transgenic mice was irradiated with 5 Gy of 300 keV X-rays, and changes in out-of-field lung and liver were observed. Results: Compared with sham-treated controls, the Spi− mutation frequency increased 2.4-fold in non-targeted lung tissues at 24 h after partial body irradiation (PBIR). Consistent with dramatic Cyclooxygenase 2 (COX-2) induction in the non-targeted bronchial epithelial cells, increasing levels of prostaglandin, together with 8-hydroxydeoxyguanosine, in the out-of-field lung tissues were observed after PBIR. In addition, DNA double-strand breaks and apoptosis were induced in bystander lung tissues after PBIR. Conclusion: The PBIR induces DNA damage and mutagenesis in non-targeted lung tissues, especially in bronchial epithelial cells, and COX-2 has an essential role in bystander mutagenesis. PMID:23321513

Biomagnification and tissue distribution of perfluoroalkyl substances (PFASs) in market-size rainbow trout (Oncorhynchus mykiss).

PubMed

Goeritz, Ina; Falk, Sandy; Stahl, Thorsten; Schäfers, Christoph; Schlechtriem, Christian

2013-09-01

The present study investigated the biomagnification potential as well as the substance and tissue-specific distribution of perfluoroalkyl substances (PFASs) in market-size rainbow trout (Oncorhynchus mykiss). Rainbow trout with an average body weight of 314 ± 21 g were exposed to perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) in the diet for 28 d. The accumulation phase was followed by a 28-d depuration phase, in which the test animals were fed with nonspiked trout feed. On days 0, 7, 14, 28, 31, 35, 42, and 56 of the present study, fish were sampled from the test basin for PFAS analysis. Biomagnification factors (BMFs) for all test compounds were determined based on a kinetic approach. Distribution factors were calculated for each test compound to illustrate the disposition of PFASs in rainbow trout after 28 d of exposure. Dietary exposure of market-size rainbow trout to PFASs did not result in biomagnification; BMF values were calculated as 0.42 for PFOS, >0.23 for PFNA, >0.18 for PFHxS, >0.04 for PFOA, and >0.02 for PFBS, which are below the biomagnification threshold of 1. Liver, blood, kidney, and skin were identified as the main target tissues for PFASs in market-size rainbow trout. Evidence was shown that despite relative low PFAS contamination, the edible parts of the fish (the fillet and skin) can significantly contribute to the whole-body burden. Copyright © 2013 SETAC.

New conceptual method for directly cooling the target biological tissues

NASA Astrophysics Data System (ADS)

Ji, Yan; Liu, Jing

2005-01-01

Hypothermia is a commonly adopted strategy to decrease the cerebral oxygen demands, which is critical for the patient to sustain longer time when subjected to a hypoxia. However, when circulatory arrest occurs, the traditional approaches such as selective brain cooling (SBC), systemic body cooling or perfusing cool blood are often not very helpful due to their slow cooling rates in preventing the tendency of a slight cerebral temperature increase at the onset of circulatory arrest. To resolve such difficult issue, a new conceptual volumetric cooling method (VCM) through minimally invasive injection of physiological coolant was proposed in this study. A heat and fluid transport model based on porous medium configuration was established to describe the thermal responses of brain tissues during hypothermia resuscitation. Theoretical calculations indicated that VCM could significantly improve the cooling rate in the deep part of the biological tissues within a desired period of time. To further test this approach, a series of either in vitro or in vivo animal experiments were performed, which also strongly supported the theoretical predictions and indicated that VCM was well appropriate for the localized cooling of target tissues. The concept of the present VCM could also possibly be extended to more wide clinical situations, when an instant and highly localized cooling for the specific organs or tissues are urgently requested. It also raised challenging issues such as injury or negative effect for the clinical operation of this VCM, which need to be addressed in the coming study.

Identification of regulatory targets of tissue-specific transcription factors: application to retina-specific gene regulation

PubMed Central

Qian, Jiang; Esumi, Noriko; Chen, Yangjian; Wang, Qingliang; Chowers, Itay; Zack, Donald J.

2005-01-01

Identification of tissue-specific gene regulatory networks can yield insights into the molecular basis of a tissue's development, function and pathology. Here, we present a computational approach designed to identify potential regulatory target genes of photoreceptor cell-specific transcription factors (TFs). The approach is based on the hypothesis that genes related to the retina in terms of expression, disease and/or function are more likely to be the targets of retina-specific TFs than other genes. A list of genes that are preferentially expressed in retina was obtained by integrating expressed sequence tag, SAGE and microarray datasets. The regulatory targets of retina-specific TFs are enriched in this set of retina-related genes. A Bayesian approach was employed to integrate information about binding site location relative to a gene's transcription start site. Our method was applied to three retina-specific TFs, CRX, NRL and NR2E3, and a number of potential targets were predicted. To experimentally assess the validity of the bioinformatic predictions, mobility shift, transient transfection and chromatin immunoprecipitation assays were performed with five predicted CRX targets, and the results were suggestive of CRX regulation in 5/5, 3/5 and 4/5 cases, respectively. Together, these experiments strongly suggest that RP1, GUCY2D, ABCA4 are novel targets of CRX. PMID:15967807

Distribution, composition and functions of gelatinous tissues in deep-sea fishes.

PubMed

Gerringer, Mackenzie E; Drazen, Jeffrey C; Linley, Thomas D; Summers, Adam P; Jamieson, Alan J; Yancey, Paul H

2017-12-01

Many deep-sea fishes have a gelatinous layer, or subdermal extracellular matrix, below the skin or around the spine. We document the distribution of gelatinous tissues across fish families (approx. 200 species in ten orders), then review and investigate their composition and function. Gelatinous tissues from nine species were analysed for water content (96.53 ± 1.78% s.d.), ionic composition, osmolality, protein (0.39 ± 0.23%), lipid (0.69 ± 0.56%) and carbohydrate (0.61 ± 0.28%). Results suggest that gelatinous tissues are mostly extracellular fluid, which may allow animals to grow inexpensively. Further, almost all gelatinous tissues floated in cold seawater, thus their lower density than seawater may contribute to buoyancy in some species. We also propose a new hypothesis: gelatinous tissues, which are inexpensive to grow, may sometimes be a method to increase swimming efficiency by fairing the transition from trunk to tail. Such a layer is particularly prominent in hadal snailfishes (Liparidae); therefore, a robotic snailfish model was designed and constructed to analyse the influence of gelatinous tissues on locomotory performance. The model swam faster with a watery layer, representing gelatinous tissue, around the tail than without. Results suggest that the tissues may, in addition to providing buoyancy and low-cost growth, aid deep-sea fish locomotion.

Distribution, composition and functions of gelatinous tissues in deep-sea fishes

PubMed Central

Drazen, Jeffrey C.; Linley, Thomas D.; Summers, Adam P.; Jamieson, Alan J.; Yancey, Paul H.

2017-01-01

Many deep-sea fishes have a gelatinous layer, or subdermal extracellular matrix, below the skin or around the spine. We document the distribution of gelatinous tissues across fish families (approx. 200 species in ten orders), then review and investigate their composition and function. Gelatinous tissues from nine species were analysed for water content (96.53 ± 1.78% s.d.), ionic composition, osmolality, protein (0.39 ± 0.23%), lipid (0.69 ± 0.56%) and carbohydrate (0.61 ± 0.28%). Results suggest that gelatinous tissues are mostly extracellular fluid, which may allow animals to grow inexpensively. Further, almost all gelatinous tissues floated in cold seawater, thus their lower density than seawater may contribute to buoyancy in some species. We also propose a new hypothesis: gelatinous tissues, which are inexpensive to grow, may sometimes be a method to increase swimming efficiency by fairing the transition from trunk to tail. Such a layer is particularly prominent in hadal snailfishes (Liparidae); therefore, a robotic snailfish model was designed and constructed to analyse the influence of gelatinous tissues on locomotory performance. The model swam faster with a watery layer, representing gelatinous tissue, around the tail than without. Results suggest that the tissues may, in addition to providing buoyancy and low-cost growth, aid deep-sea fish locomotion. PMID:29308245

Distribution of simian immunodeficiency virus target cells in vaginal tissues of normal rhesus macaques: implications for virus transmission.

PubMed

Poonia, Bhawna; Wang, Xiaolei; Veazey, Ronald S

2006-12-01

Most new cases of HIV-1 infection occur as the result of vaginal transmission. Identifying the phenotype and distribution of potential viral target cells in the vagina is important for understanding events in viral transmission and for developing effective prevention strategies. For example, compounds that prevent CD4 or CCR5 binding have been demonstrated recently to prevent vaginal transmission in rhesus macaques, but the expression and distribution of CCR5 has not been examined in the macaque vagina. The objective of this study was to examine the distribution and phenotype of cells and molecules in the vagina of rhesus macaques that may be involved in HIV transmission, including CCR5, CD3, CD4, CD8, CD1a, CD28, CD95, CD123 and HLA-DR. Normal juvenile and adult female rhesus macaques were examined by multicolor immunohistochemistry and flow cytometry. Although both CD4 and CCR5 were observed in the lamina propria, essentially no CD4 or CCR5 expression was detected within the squamous or keratinized layers of the vaginal epithelium. CCR5 expression was higher in the vaginal lamina propria of mature macaques compared to 1-3-year-old juveniles. The vast majority of CD4(+)CCR5(+) lymphocytes in the vagina had a central memory (CD95(+)CD28(+)) phenotype. Numerous CCR5-expressing dendritic cells (CD123(+)) or macrophages (CD68(+)) were observed in the lamina propria, but no CCR5, CD4 or DC-SIGN expression was detectable in the epithelium. Thus, the multiple layers of squamous epithelium normally covering the vaginal mucosa may provide an effective barrier against vaginal HIV-1 transmission. Microbicides that block CD4 or CCR5 expression may act within the deeper layers of the vaginal epithelium rather than on the epithelial surface.

Crustacean hyperglycemic hormone (CHH) neuropeptidesfamily: Functions, titer, and binding to target tissues.

PubMed

Chung, J Sook; Zmora, N; Katayama, H; Tsutsui, N

2010-05-01

The removal of the eyestalk (s) induces molting and reproduction promoted the presence of regulatory substances in the eyestalk (ES), particularly medulla terminalis X-organ and the sinus gland (MTXO-SG). The PCR-based cloning strategies have allowed for isolating a great number of cDNAs sequences of crustacean hyperglycemic hormone (CHH) neuropeptides family from the eyestalk and non-eyestalk tissues, e.g., pericardial organs and fore- and hindguts. However, the translated corresponding neuropeptides in these tissues, their circulating concentrations, the mode of actions, and specific physiological functions have not been well described. The profiles of CHH neuropeptides present in the MTXO-SG may differ among decapod crustacean species, but they can be largely divided into two sub-groups on the basis of structural homology: (1) CHH and (2) molt-inhibiting hormone (MIH)/mandibular organ-inhibiting hormone (MOIH)/vitellogenesis/gonad-inhibiting hormone (V/GIH). CHH typically elevating the level of circulating glucose from animals under stressful conditions (hyper- and hypothermia, hypoxia, and low salinity) has multiple target tissues and functions such as ecdysteroidogenesis, osmoregulation, and vitellogenesis. Recently, MIH, known for exclusively suppressing ecdysteroidogenesis in Y-organs, is also reported to have an additional role in vitellogenesis of adult female crustacean species, suggesting that some CHH neuropeptides may acquire an extra regulatory role in reproduction at adult stage. This paper reviews the regulatory roles of CHH and MIH at the levels of specific functions, temporal and spatial expression, titers, their binding sites on the target tissues, and second messengers from two crab species: the blue crab, Callinectes sapidus, and the European green crab, Carcinus maenas. It further discusses the diverse regulatory roles of these neuropeptides and the functional plasticity of these neuropeptides in regard to life stage and species

ASSESSING FISH TISSUE CONTAMINATION ON A REGIONAL SCALE

EPA Science Inventory

The selection of target fish species for assessing the extent of fish tissue contaminants is a critical consideration in regional stream surveys such as the Environmental Monitoring and Assessment Program (EMAP). The ideal species would be widely distributed and common, bioaccumu...

A liquid chromatography-tandem mass spectrometry-based targeted proteomics assay for monitoring P-glycoprotein levels in human breast tissue.

PubMed

Yang, Ting; Chen, Fei; Xu, Feifei; Wang, Fengliang; Xu, Qingqing; Chen, Yun

2014-09-25

P-glycoprotein (P-gp) can efflux drugs from cancer cells, and its overexpression is commonly associated with multi-drug resistance (MDR). Thus, the accurate quantification of P-gp would help predict the response to chemotherapy and for prognosis of breast cancer patients. An advanced liquid chromatography-tandem mass spectrometry (LC/MS/MS)-based targeted proteomics assay was developed and validated for monitoring P-gp levels in breast tissue. Tryptic peptide 368IIDNKPSIDSYSK380 was selected as a surrogate analyte for quantification, and immuno-depleted tissue extract was used as a surrogate matrix. Matched pairs of breast tissue samples from 60 patients who were suspected to have drug resistance were subject to analysis. The levels of P-gp were quantified. Using data from normal tissue, we suggested a P-gp reference interval. The experimental values of tumor tissue samples were compared with those obtained from Western blotting and immunohistochemistry (IHC). The result indicated that the targeted proteomics approach was comparable to IHC but provided a lower limit of quantification (LOQ) and could afford more reliable results at low concentrations than the other two methods. LC/MS/MS-based targeted proteomics may allow the quantification of P-gp in breast tissue in a more accurate manner. Copyright © 2014 Elsevier B.V. All rights reserved.

Distribution of Tocopherols and Tocotrienols in Guinea Pig Tissues Following Parenteral Lipid Emulsion Infusion.

PubMed

Xu, Zhidong; Harvey, Kevin A; Pavlina, Thomas M; Zaloga, Gary P; Siddiqui, Rafat A

2016-07-01

Tocopherols and tocotrienols possess vitamin E activity and function as the major lipid-soluble antioxidants in the human body. Commercial lipid emulsions are composed of different oils and supply different amounts of vitamin E. The objective of this study was to measure all 8 vitamin E homologs within 4 different commercial lipid emulsions and evaluate their distribution in guinea pig tissues. The distribution of vitamin E homologs within plasma and guinea pig tissues was determined using a high-performance liquid chromatography (HPLC) system. Lipid hydroperoxides in lipid emulsions were determined using a commercial kit (Cayman Chemical Company, Ann Arbor, MI), and malondialdehyde tissue levels were determined using an HPLC system. The lipid emulsions contained variable amounts of tocopherols, which were significantly different between emulsions. Tocotrienols were present at very low concentrations (≤0.3%). We found no correlation between the amount of vitamin E present in the lipid emulsions and lipid peroxidation. Hydroperoxides were the lowest with an olive oil-based emulsion and highest with a fish oil emulsion. The predominant vitamin E homolog in guinea pig tissues was α-tocopherol. No tissues had detectable levels of tocotrienols. Vitamin E levels (primarily α-tocopherol and γ-tocopherol) were highly variable among organ tissues. Plasma levels were a poor reflection of most tissue levels. Vitamin E levels within different lipid emulsions and plasma/tissues are highly variable, and no one tissue or plasma sample serves as a good proxy for levels in other tissues. All study emulsions were well tolerated and did not significantly increase systemic lipid peroxidation. © 2014 American Society for Parenteral and Enteral Nutrition.

The tissue distribution and excretion study of paeoniflorin-6'-O-benzene sulfonate (CP-25) in rats.

PubMed

Zhao, Mingyi; Zhou, Peng; Yu, Jun; James, Asenso; Xiao, Feng; Wang, Chun; Wei, Wei

2018-03-09

Paeoniflorin-6'-O-benzene sulfonate (code: CP-25) is a novel ester derivative of paeoniflorin (Pae). Compared to Pae, CP-25 has higher lipid solubility, bioavailability and better bioactivity. However, the tissue distribution and excretion of CP-25 still remain unknown. The LC-MS method was applied to investigate the tissue distribution and excretion of CP-25 in rats. As such, 50 mg/kg of CP-25 and Pae were administered to rats in multiple doses via an oral route. CP-25 and Pae were distributed widely and rapidly in all the tested tissues. Compared with Pae, the concentrations of CP-25 were almost increased evidently in most tissues. The highest CP-25 level was found in the liver (1476.33 ± 535.20 ng/g, male; 1970.38 ± 177.21 ng/g, female) at 3 h, and a high concentration of CP-25 was detected in male and female intestine, synovium, muscle, lung, and brain. Following a single oral dose of 50 mg/kg of CP-25 in rats, the total excretion of CP-25 was merely 21.8% (18.40, 3.19 and 0.22% for feces, bile and urine, respectively) in males; and was approximately 21.3% (14.04, 7.16 and 0.14% for feces, bile and urine, respectively) in females. The results indicated that the CP-25 concentration was higher in major tissues than Pae; CP-25 was primarily excreted through the feces; and there were gender-related differences in the tissue distribution and excretion.

Reagent Precoated Targets for Rapid In-Tissue Derivatization of the Anti-Tuberculosis Drug Isoniazid Followed by MALDI Imaging Mass Spectrometry

NASA Astrophysics Data System (ADS)

Manier, M. Lisa; Reyzer, Michelle L.; Goh, Anne; Dartois, Veronique; Via, Laura E.; Barry, Clifton E.; Caprioli, Richard M.

2011-08-01

Isoniazid (INH) is an important component of front-line anti-tuberculosis therapy with good serum pharmacokinetics but unknown ability to penetrate tuberculous lesions. However, endogenous background interferences hinder our ability to directly analyze INH in tissues. Chemical derivatization has been successfully used to measure isoniazid directly from tissue samples using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS). MALDI targets were pretreated with trans-cinnamaldehyde (CA) prior to mounting tissue slices. Isoniazid present in the tissues was efficiently derivatized and the INH-CA product measured by MS/MS. Precoating of MALDI targets allows the tissues to be directly thaw-mounted and derivatized, thus simplifying the preparation. A time-course series of tissues from tuberculosis infected/INH dosed animals were assayed and the MALDI MS/MS response correlates well with the amount of INH determined to be in the tissues by high-performance liquid chromatography (HPLC)-MS/MS.

The Tissue Distribution and Urinary Excretion Study of Gallic Acid and Protocatechuic Acid after Oral Administration of Polygonum Capitatum Extract in Rats.

PubMed

Ma, Feng-Wei; Deng, Qing-Fang; Zhou, Xin; Gong, Xiao-Jian; Zhao, Yang; Chen, Hua-Guo; Zhao, Chao

2016-03-24

In the present study, we investigated the tissue distribution and urinary excretion of gallic acid (GA) and protocatechuic acid (PCA) after rat oral administration of aqueous extract of Polygonum capitatum (P. capitatum, named Herba Polygoni Capitati in China). An UHPLC-MS/MS analytical method was developed and adopted for quantification of GA and PCA in different tissue homogenate and urine samples. Interestingly, we found that GA and PCA showed a relatively targeted distribution in kidney tissue after dosing 60 mg/kg P. capitatum extract (equivalent to 12 mg/kg of GA and 0.9 mg/kg of PCA). The concentrations of GA and PCA in the kidney tissue reached 1218.62 ng/g and 43.98 ng/g, respectively, at one hour after oral administration. The results helped explain the empirical use of P. capitatum for kidney diseases in folk medicine. Further studies on urinary excretion of P. capitatum extract indicated that GA and PCA followed a concentrated elimination over a 4-h period. The predominant metabolites were putatively identified to be 4-methylgallic acid (4-OMeGA) and 4-methylprotocatechuic acid (4-OMePCA) by analyzing their precursor ions and characteristic fragment ions using tandem mass spectrometry. However, the amount of unchanged GA and PCA that survived the metabolism were about 14.60% and 15.72% of the total intake, respectively, which is reported for the first time in this study.

Subcellular localization and distribution of the reduced folate carrier in normal rat tissues.

PubMed

Hinken, M; Halwachs, S; Kneuer, C; Honscha, W

2011-01-27

The reduced folate carrier (Rfc1; Slc19a1) mediated transport of reduced folates and antifolate drugs such as methotrexate (MTX) play an essential role in physiological folate homeostasis and MTX cancer chemotherapy. As no systematic reports are as yet available correlating Rfc1 gene expression and protein levels in all tissues crucial for folate and antifolate uptake, storage or elimination, we investigated gene and protein expression of rat Rfc1 (rRfc1) in selected tissues. This included the generation of a specific anti-rRfc1 antibody. Rabbits were immunised with isolated rRfc1 peptides producing specific anti-rRfc1 antiserum targeted to the intracellular C-terminus of the carrier. Using RT-PCR analysis, high rRfc1 transcript levels were detected in colon, kidney, brain, thymus, and spleen. Moderate rRfc1 gene expression was observed in small intestine, liver, bone marrow, lung, and testes whereas transcript levels were negligible in heart, skeletal muscle or leukocytes. Immunohistochemical analyses revealed strong carrier expression in the apical membrane of tunica mucosa epithelial cells of small intestine and colon, in the brush-border membrane of choroid plexus epithelial cells or in endothelial cells of small vessels in brain and heart. Additionally, high rRfc1 protein levels were localized in the basolateral membrane of renal tubular epithelial cells, in the plasma membrane of periportal hepatocytes, and sertoli cells of the testes. Taken together, our results demonstrated that rRfc1 is expressed almost ubiquitously but to very different levels. The predominant tissue distribution supports the essential role of Rfc1 in physiological folate homeostasis. Moreover, our results may contribute to understand antifolate pharmacokinetics and selected organ toxicity associated with MTX chemotherapy.

Acoustic Droplet Vaporization and Propulsion of Perfluorocarbon-Loaded Microbullets for Targeted Tissue Penetration and Deformation

PubMed Central

Kagan, Daniel; Benchimol, Michael J.; Claussen, Jonathan C.; Chuluun-Erdene, Erdembileg

2012-01-01

Acoustic droplet vaporization of perfluorocarbon-loaded microbullets triggered by an ultrasound pulse provides the necessary force to penetrate, cleave, and deform cellular tissue for potential targeted drug delivery and precision nanosurgery. PMID:22692791

Distribution and Depletion of Ractopamine in Goat Plasma, Urine and Various Muscle Tissues.

PubMed

Zhao, Zhen; Gu, Xu; Su, Xiaoou; Li, Junguo; Li, Jun; Dong, Yingchao; Yang, Yujuan; Yao, Ting; Qin, Yuchang

2017-01-01

This study investigated the ractopamine (RAC) distribution and depletion process in goat plasma, urine and various muscle tissues which were associated with a potential risk for consumer health. The experiment was carried out in 21 goats (18 treated and 3 controls). Treated animals were administered orally a dose of 1 mg/kg body mass per day for 28 consecutive days and randomly sacrificed on Days 0.25, 1, 3, 7, 14 and 21 of the withdrawal period. RAC in goat samples was analyzed by using ultra-high performance liquid chromatography-quadrupole-orbitrap high-resolution mass spectrometry. RAC was below the limits of detection (LOD = 0.15 ng/mL) in plasma while which was higher than the LOD in urine on withdrawal day 21. The residues in goat longissimus dorsi muscle, biceps femoris muscle and triceps surae muscle were differed significantly. These findings demonstrated that urine can be used as the target matrix for monitoring RAC abuse in goat. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Comparative Kinetics and Distribution to Target Tissues of Organophosphates Using Physiologically - Based Pharmacokinetic Modeling

DTIC Science & Technology

2008-03-01

throughout history where nerve agents have been used on human populations, such as the subway bombing in Tokyo and Matsumoto, Japan. Data can be...kidney, fat, diaphragm, arterial blood, venous blood, bronchial passages, and the skin. The remaining tissues will be lumped together as either slowly...were then further developed as a weapon, whose primary effect is on the central nervous system. These agents are tabun, sarin, soman, and VX. They

Ocular tissue distribution and pharmacokinetic study of a small 13kDa domain antibody after intravitreal, subconjuctival and eye drop administration in rabbits.

PubMed

Gough, Gerald; Szapacs, Matthew; Shah, Tejash; Clements, Peter; Struble, Craig; Wilson, Robert

2018-02-01

Domain antibodies (dAb's) comprise the smallest functional unit of human IgG and can be targeted to a range of different soluble cytokine and receptor targets in the eye. In particular their small size may offer advantage for ocular tissue penetration and distribution. To investigate this we used a 13kDa tool molecule to undertake a preliminary short term ocular tissue distribution and pharmacokinetic study in the rabbit eye. The dAb was administered by the intravitreal or subconjunctival route or, as topical eye drops for up to five days and dAb concentrations measured in vitreous, aqueous, conjunctiva, choroid-RPE, retina, iris, sclera, and ciliary body. The observed elimination half-live of the dAb (~3 days) in vitreous showed a similar elimination rate to that of a much larger (∼50kDa) Fab fragment whilst the half-life following subconjunctival administration was ∼24 h and, after eye drop dosing the dAb was detectable in aqueous and conjunctiva. These preliminary data show that the intravitreal half-life of dAb's are similar to much larger antibody fragments, offering the potential to deliver significantly more drug to target on a molar basis with a single intravitreal injection potentially enabling dosing frequencies of once a month or less. Subconjunctival injection may provide short duration therapeutic levels of dAb to the anterior and posterior chamber whilst topical eye drop delivery of dAbs may be useful in front-of-eye disease. These data indicate that small domain antibodies may have utility in ophthalmology. Further studies are warranted. Copyright © 2017 Elsevier Ltd. All rights reserved.

Obtaining source current density related to irregularly structured electromagnetic target field inside human body using hybrid inverse/FDTD method.

PubMed

Han, Jijun; Yang, Deqiang; Sun, Houjun; Xin, Sherman Xuegang

2017-01-01

Inverse method is inherently suitable for calculating the distribution of source current density related with an irregularly structured electromagnetic target field. However, the present form of inverse method cannot calculate complex field-tissue interactions. A novel hybrid inverse/finite-difference time domain (FDTD) method that can calculate the complex field-tissue interactions for the inverse design of source current density related with an irregularly structured electromagnetic target field is proposed. A Huygens' equivalent surface is established as a bridge to combine the inverse and FDTD method. Distribution of the radiofrequency (RF) magnetic field on the Huygens' equivalent surface is obtained using the FDTD method by considering the complex field-tissue interactions within the human body model. The obtained magnetic field distributed on the Huygens' equivalent surface is regarded as the next target. The current density on the designated source surface is derived using the inverse method. The homogeneity of target magnetic field and specific energy absorption rate are calculated to verify the proposed method.

[Diversity and tissue distribution of fungal endophytes in Alpinia officinarum: an important south-China medicinal plant].

PubMed

Zhou, Ren-Chao; Huang, Juan; Li, Ze-En; Li, Shu-Bin

2014-08-01

In the present study, terminal-restriction fragment length polymorphism (T-RFLP) technique was applied to assess the diversity and tissue distribution of the fungal endophyte communities of Alpinia officinarum collected from Longtang town in Xuwen county, Guangdong province, China, at which the pharmacological effect of the medicine plant is traditional considered to be the significantly higher than that in any other growth areas in China. A total of 28 distinct Terminal-Restriction Fragment (T-RFs) were detected with HhaI Mono-digestion targeted amplified fungal nuclear ribosomal internal transcribed spacer region sequences (rDNA ITS) from the root, rhizome, stem, and leaf internal tissues of A. officinarum plant, indicating that at least 28 distinct fungal species were able to colonize the internal tissue of the host plant. The rDNA ITS-T-RFLP profiles obtained from different tissues of the host plant were obvious distinct. And the numbers of total T-RFs, and the dominant T-RFs detected from various tissues were significantly different. Based on the obtained T-RFLP profiles, Shannon's diversity index and the Shannon's evenness index were calculated, which were significantly different among tissues (P < 0.05). Furthermore, two types of active chemicals, total volatile oils by water vapor distillation method and galangin by methanol extraction-HPLC method, were examined in the each tissue of the tested plant. Both of tested components were detected in all of the four tissues of the medicine plant with varying contents. And the highest was in rhizome tissue. Correlation analysis revealed there were significant negative correlations between both of the tested active components contents and calculated Shannon's diversity index, as well as the Shannon's evenness index of the fungal endophyte communities of the host plant (P = 0, Pearson correlation coefficient ≤ -0.962), and significant positive correlations between both of the tested active components contents and

TU-F-18C-05: Evaluation of a Method to Calculate Patient-Oriented MGD Coefficients Using Estimates of Glandular Tissue Distribution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Porras-Chaverri, M; University of Costa Rica, San Jose; Galavis, P

Purpose: Evaluate mammographic mean glandular dose (MGD) coefficients for particular known tissue distributions using a novel formalism that incorporates the effect of the heterogeneous glandular tissue distribution, by comparing them with MGD coefficients derived from the corresponding anthropomorphic computer breast phantom. Methods: MGD coefficients were obtained using MCNP5 simulations with the currently used homogeneous assumption and the heterogeneously-layered breast (HLB) geometry and compared against those from the computer phantom (ground truth). The tissue distribution for the HLB geometry was estimated using glandularity map image pairs corrected for the presence of non-glandular fibrous tissue. Heterogeneity of tissue distribution was quantified usingmore » the glandular tissue distribution index, Idist. The phantom had 5 cm compressed breast thickness (MLO and CC views) and 29% whole breast glandular percentage. Results: Differences as high as 116% were found between the MGD coefficients with the homogeneous breast core assumption and those from the corresponding ground truth. Higher differences were found for cases with more heterogeneous distribution of glandular tissue. The Idist for all cases was in the [−0.8{sup −}+0.3] range. The use of the methods presented in this work results in better agreement with ground truth with an improvement as high as 105 pp. The decrease in difference across all phantom cases was in the [9{sup −}105] pp range, dependent on the distribution of glandular tissue and was larger for the cases with the highest Idist values. Conclusion: Our results suggest that the use of corrected glandularity image pairs, as well as the HLB geometry, improves the estimates of MGD conversion coefficients by accounting for the distribution of glandular tissue within the breast. The accuracy of this approach with respect to ground truth is highly dependent on the particular glandular tissue distribution studied. Predrag Bakic

Consequences of additional use of PET information for target volume delineation and radiotherapy dose distribution for esophageal cancer.

PubMed

Muijs, Christina T; Schreurs, Liesbeth M; Busz, Dianne M; Beukema, Jannet C; van der Borden, Arnout J; Pruim, Jan; Van der Jagt, Eric J; Plukker, John Th; Langendijk, Johannes A

2009-12-01

To determine the consequences of target volume (TV) modifications, based on the additional use of PET information, on radiation planning, assuming PET/CT-imaging represents the true extent of the tumour. For 21 patients with esophageal cancer, two separate TV's were retrospectively defined based on CT (CT-TV) and co-registered PET/CT images (PET/CT-TV). Two 3D-CRT plans (prescribed dose 50.4 Gy) were constructed to cover the corresponding TV's. Subsequently, these plans were compared for target coverage, normal tissue dose-volume histograms and the corresponding normal tissue complication probability (NTCP) values. The addition of PET led to the modification of CT-TV with at least 10% in 12 of 21 patients (57%) (reduction in 9, enlargement in 3). PET/CT-TV was inadequately covered by the CT-based treatment plan in 8 patients (36%). Treatment plan modifications resulted in significant changes (p<0.05) in dose distributions to heart and lungs. Corresponding changes in NTCP values ranged from -3% to +2% for radiation pneumonitis and from -0.2% to +1.2% for cardiac mortality. This study demonstrated that TV's based on CT might exclude PET-avid disease. Consequences are under dosing and thereby possibly ineffective treatment. Moreover, the addition of PET in radiation planning might result in clinical important changes in NTCP.

An estimation of distribution method for infrared target detection based on Copulas

NASA Astrophysics Data System (ADS)

Wang, Shuo; Zhang, Yiqun

2015-10-01

Track-before-detect (TBD) based target detection involves a hypothesis test of merit functions which measure each track as a possible target track. Its accuracy depends on the precision of the distribution of merit functions, which determines the threshold for a test. Generally, merit functions are regarded Gaussian, and on this basis the distribution is estimated, which is true for most methods such as the multiple hypothesis tracking (MHT). However, merit functions for some other methods such as the dynamic programming algorithm (DPA) are non-Guassian and cross-correlated. Since existing methods cannot reasonably measure the correlation, the exact distribution can hardly be estimated. If merit functions are assumed Guassian and independent, the error between an actual distribution and its approximation may occasionally over 30 percent, and is divergent by propagation. Hence, in this paper, we propose a novel estimation of distribution method based on Copulas, by which the distribution can be estimated precisely, where the error is less than 1 percent without propagation. Moreover, the estimation merely depends on the form of merit functions and the structure of a tracking algorithm, and is invariant to measurements. Thus, the distribution can be estimated in advance, greatly reducing the demand for real-time calculation of distribution functions.

Mechanisms involved in the transport of mercuric ions in target tissues

PubMed Central

Bridges, Christy C.; Zalups, Rudolfs K.

2016-01-01

Mercury exists in the environment in various forms, all of which pose a risk to human health. Despite guidelines regulating the industrial release of mercury into the environment, humans continue to be exposed regularly to various forms of this metal via inhalation or ingestion. Following exposure, mercuric ions are taken up by and accumulate in numerous organs, including brain, intestine, kidney, liver, and placenta. In order to understand the toxicological effects of exposure to mercury, a thorough understanding of the mechanisms that facilitate entry of mercuric ions into target cells must first be obtained. A number of mechanisms for the transport of mercuric ions into target cells and organs have been proposed in recent years. However, the ability of these mechanisms to transport mercuric ions and the regulatory features of these carriers have not been characterized completely. The purpose of this review is to summarize the current findings related to the mechanisms that may be involved in the transport of inorganic and organic forms of mercury in target tissues and organs. This review will describe mechanisms known to be involved in the transport of mercury and will also propose additional mechanisms that may potentially be involved in the transport of mercuric ions into target cells. PMID:27422290

Mitomycin C dissolved in a reversible thermosetting gel: target tissue concentrations in the rabbit eye.

PubMed

Ichien, K; Yamamoto, T; Kitazawa, Y; Oguri, A; Ando, H; Kondo, Y

1997-01-01

To determine whether a new, reversible thermosetting gel enhances mitomycin C transfer to target ocular tissues in the rabbit eye. A 0.1 ml solution of mitomycin C containing 0.22 microgram, 2.9 micrograms, or 28 micrograms of the agent dissolved in a reversible thermosetting gel consisting of methylcellulose, citric acid, and polyethylene glycol was injected subconjunctivally in 30 New Zealand albino rabbits. Scleral and conjunctival tissues were excised at 0.5, 1, 2, 4, or 24 hours after the injection and mitomycin C concentrations in these tissues were determined by high performance liquid chromatography. The concentration over time was approximated to a single exponential curve, and initial mitomycin C concentrations, time constants, and half life values were determined. Finally, the areas under the curves (AUCs) between 0.5 and 24 hours were calculated. The mitomycin C concentrations in the target tissues were dose dependent and decreased rapidly over 24 hours. Both the initial mitomycin C concentrations as well as AUCs in these eyes treated with mitomycin C, dissolved in a reversible thermosetting gel, were higher than those in eyes treated similarly in a previous study in which the gel was not used. Applied subconjunctivally in the rabbit eye, mitomycin C dissolved in the reversible thermosetting gel enhanced transfer of the agent to the sclera and the conjunctiva.

Accumulation and distribution of selenium in mussel and shrimp tissues

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fowler, S.W.; Benayoun, G.

1976-09-01

The tissue distribution of selenium in mussels and shrimp was examined and the bioaccumulation kinetics in the various tissues was elucidated with the aid of radio selenium. Mussels (Mytilus galloprovincialis) and shrimp (Lysmata seticaudata) collected near the Monaco port, were apportioned into several groups. One group of mussels and shrimp was maintained in sea water containing 0.8 ..mu..Ci/liter high specific activity Se-75. Three to four individuals were dissected and their tissues monitored for Se-75 content periodically. Another group of shrimp, maintained in flowing sea water, were fed ad libitum mussels that had previously accumulated Se-75 from sea water for severalmore » days. Shrimp were periodically dissected to follow tissue accumulation of ingested selenium. The highest concentrations of selenium were found in the exoskeleton, presumably due, in part, to the relatively large amount of isotope sorbed to its outer surface. Molts, cast by shrimp at various times throughout uptake, contained from 60 to 90% of the total Se-75 body burden. Direct uptake of water led to initially small fractions in internal tissues such as muscle and viscera compared to the relatively large fraction associated with the exoskeleton. With time percentages in internal tissues gradually increased relative to that in the exoskeleton. When Se-75 was accumulated through the food chain an opposite trend was noted with the Se-75 fraction in exoskeleton slowly increasing and that in viscera decreasing during the course of the experiment. All tissues examined readily accumulated the isotope and, in general, did not appear to have reached a steady state concentration after 63 days. The highest Se-75 concentrations were found in the visceral mass with lesser amounts in gills, muscle and mantle, in that order.« less

Testing methods of pressure distribution of bra cups on breasts soft tissue

NASA Astrophysics Data System (ADS)

Musilova, B.; Nemcokova, R.; Svoboda, M.

2017-10-01

Objective of this study is to evaluate testing methods of pressure distribution of bra cups on breasts soft tissue, the system which do not affect the space between the wearer's body surface and bra cups and thus do not influence the geometry of the measured body surface and thus investigate the functional performance of brassieres. Two measuring systems were used for the pressure comfort evaluating: 1) The pressure distribution of a wearing bra during 20 minutes on women's breasts has been directly measured using pressure sensor, a dielectricum which is elastic polyurethane foam bra cups. Twelve points were measured in bra cups. 2) Simultaneously the change of temperature in the same points bra was tested with the help of noncontact system the thermal imager. The results indicate that both of those systems can identify different pressure distribution at different points. The same size of bra designing features bra cups made from the same material and which is define by the help of same standardised body dimensions (bust and underbust) can cause different value of a compression on different shape of a woman´s breast soft tissue.

Distribution of the lingual lymphoid tissue in domestic ruminants.

PubMed

Breugelmans, S; Casteleyn, C; Simoens, P; Van den Broeck, W

2011-12-01

The distribution and organisation of the intralingual lymphoid tissue was studied in sheep, goat and cattle. For each species, the tongues of two animals were harvested and divided in sample blocks extending over the total surface of the tongue. With 2.5 mm intervals, ten serial histological sections were made for conventional histological staining (haematoxylin-eosin, Van Gieson, Masson's trichrome) and immunohistochemical staining of lymphoid cells (anti-CD3, anti-CD21, anti-CD45). Lymphocytes were scattered in the subepithelial propria-submucosa and in the connective tissue cores of the lingual papillae. The connective tissue cores of fungiform papillae, including those located on the lingual apex, and vallate papillae showed relatively more lymphocytes than the propria-submucosa. Lymphoid cell aggregations were even more abundant beneath the grooves surrounding the vallate papillae in small ruminants. In cattle, a well-organised lingual tonsil was additionally found at the root of the tongue. CD3-positive lymphocytes were observed in all species examined. CD21-positive lymphocytes were numerous in the lymphoid nodules of the bovine lingual tonsil but very scarce in the ovine and caprine tongues. Therefore, the lymphoid cell aggregations in the tongues of small ruminants should not be referred to by the term 'lingual tonsil'. © 2011 Blackwell Verlag GmbH.

Targeted therapies in cancer - challenges and chances offered by newly developed techniques for protein analysis in clinical tissues

PubMed Central

Malinowsky, K; Wolff, C; Gündisch, S; Berg, D; Becker, KF

2011-01-01

In recent years, new anticancer therapies have accompanied the classical approaches of surgery and radio- and chemotherapy. These new forms of treatment aim to inhibit specific molecular targets namely altered or deregulated proteins, which offer the possibility of individualized therapies. The specificity and efficiency of these new approaches, however, bring about a number of challenges. First of all, it is essential to specifically identify and quantify protein targets in tumor tissues for the reasonable use of such targeted therapies. Additionally, it has become even more obvious in recent years that the presence of a target protein is not always sufficient to predict the outcome of targeted therapies. The deregulation of downstream signaling molecules might also play an important role in the success of such therapeutic approaches. For these reasons, the analysis of tumor-specific protein expression profiles prior to therapy has been suggested as the most effective way to predict possible therapeutic results. To further elucidate signaling networks underlying cancer development and to identify new targets, it is necessary to implement tools that allow the rapid, precise, inexpensive and simultaneous analysis of many network components while requiring only a small amount of clinical material. Reverse phase protein microarray (RPPA) is a promising technology that meets these requirements while enabling the quantitative measurement of proteins. Together with recently developed protocols for the extraction of proteins from formalin-fixed, paraffin-embedded (FFPE) tissues, RPPA may provide the means to quantify therapeutic targets and diagnostic markers in the near future and reliably screen for new protein targets. With the possibility to quantitatively analyze DNA, RNA and protein from a single FFPE tissue sample, the methods are available for integrated patient profiling at all levels of gene expression, thus allowing optimal patient stratification for

Proton Energy Optimization and Spatial Distribution Analysis from a Thickness Study Using Liquid Crystal Targets

NASA Astrophysics Data System (ADS)

Willis, Christopher; Poole, Patrick; Schumacher, Douglas; Freeman, Richard; van Woerkom, Linn

2016-10-01

Laser-accelerated ions from thin targets have been widely studied for applications including secondary radiation sources and cancer therapy, with recent studies trending towards thinner targets which can provide improved ion energies and yields. Here we discuss results from an experiment on the Scarlet laser at OSU using variable thickness liquid crystal targets. On this experiment, the spatial and spectral distributions of accelerated ions were measured along target normal and laser axes at varying thicknesses from 150nm to 2000nm at a laser intensity of 1 ×1020W /cm2 . Maximum ion energy was observed for targets in the 600 - 800nm thickness range, with proton energies reaching 24MeV . The ions were further characterized using radiochromic film, revealing an unusual spatial distribution on many laser shots. Here, the peak ion yield falls in an annular ring surrounding the target normal, with an increasing divergence angle as a function of ion energy. Details of these spatial and spectral ion distributions will be presented, including spectral deconvolution of the RCF data, revealing additional trends in the accelerated ion distributions. Supported by the DARPA PULSE program through a Grant from AMRDEC, and by the NNSA under contract DE-NA0001976.

CD13 as target for tissue factor induced tumor vascular infarction in small cell lung cancer.

PubMed

Schmidt, Lars Henning; Stucke-Ring, Janine; Brand, Caroline; Schliemann, Christoph; Harrach, Saliha; Muley, Thomas; Herpel, Esther; Kessler, Torsten; Mohr, Michael; Görlich, Dennis; Kreuter, Michael; Lenz, Georg; Wardelmann, Eva; Thomas, Michael; Berdel, Wolfgang E; Schwöppe, Christian; Hartmann, Wolfgang

2017-11-01

Zinc-binding protease aminopeptidase N (CD13) is expressed on tumor vascular cells and tumor cells. It represents a potential candidate for molecular targeted therapy, e.g. employing truncated tissue factor (tTF)-NGR, which can bind CD13 and thereby induce tumor vascular infarction. We performed a comprehensive analysis of CD13 expression in a clinically well characterized cohort of patients with small cell lung cancer (SCLC) to evaluate its potential use for targeted therapies in this disease. CD13 expression was analyzed immunohistochemically in 27 SCLC patients and correlated with clinical course and outcome. In CD-1 nude mice bearing human HTB119 SCLC xenotransplants, the systemic effects of the CD13-targeting fusion protein tTF-NGR on tumor growth were tested. In 52% of the investigated SCLC tissue samples, CD13 was expressed in tumor stroma cells, while the tumor cells were negative for CD13. No prognostic effect was found in the investigated SCLC study collective with regard to overall survival (p>0.05). In CD-1 nude mice, xenografts of CD13 negative HTB119 SCLC cells showed CD13 expression in the intratumoral vascular and perivascular cells, and the systemic application of CD13-targeted tissue factor tTF-NGR led to a significant reduction of tumor growth. We here present first data on the expression of CD13 in SCLC tumor samples. Our results strongly recommend the further investigation of tTF-NGR and other molecules targeted by NGR-peptides in SCLC patients. Considering the differential expression of CD13 in SCLC samples pre-therapeutic CD13 analysis is proposed for testing as investigational predictive biomarker for patient selection. Copyright © 2017 Elsevier B.V. All rights reserved.

Obesity alters adipose tissue macrophage iron content and tissue iron distribution.

PubMed

Orr, Jeb S; Kennedy, Arion; Anderson-Baucum, Emily K; Webb, Corey D; Fordahl, Steve C; Erikson, Keith M; Zhang, Yaofang; Etzerodt, Anders; Moestrup, Søren K; Hasty, Alyssa H

2014-02-01

Adipose tissue (AT) expansion is accompanied by the infiltration and accumulation of AT macrophages (ATMs), as well as a shift in ATM polarization. Several studies have implicated recruited M1 ATMs in the metabolic consequences of obesity; however, little is known regarding the role of alternatively activated resident M2 ATMs in AT homeostasis or how their function is altered in obesity. Herein, we report the discovery of a population of alternatively activated ATMs with elevated cellular iron content and an iron-recycling gene expression profile. These iron-rich ATMs are referred to as MFe(hi), and the remaining ATMs are referred to as MFe(lo). In lean mice, ~25% of the ATMs are MFe(hi); this percentage decreases in obesity owing to the recruitment of MFe(lo) macrophages. Similar to MFe(lo) cells, MFe(hi) ATMs undergo an inflammatory shift in obesity. In vivo, obesity reduces the iron content of MFe(hi) ATMs and the gene expression of iron importers as well as the iron exporter, ferroportin, suggesting an impaired ability to handle iron. In vitro, exposure of primary peritoneal macrophages to saturated fatty acids also alters iron metabolism gene expression. Finally, the impaired MFe(hi) iron handling coincides with adipocyte iron overload in obese mice. In conclusion, in obesity, iron distribution is altered both at the cellular and tissue levels, with AT playing a predominant role in this change. An increased availability of fatty acids during obesity may contribute to the observed changes in MFe(hi) ATM phenotype and their reduced capacity to handle iron.

Distribution of hexadecenoic, octadecenoic and octadecadienoic acid isomers in human tissue lipids.

PubMed

Adlof, R O; Emken, E A

1986-09-01

The trans 16:1, 18:1 and 18:2 fatty acid composition of various human organ lipids was studied to determine if isomers accumulated in specific tissues. "Trans" isomers are defined as those fatty acids containing one or more trans double bonds. Adipose, kidney, brain, heart and liver tissue lipids were analyzed. Gas chromatography with a 100-SP2560 capillary column was used to characterize the various positional and/or geometrical isomers. The distribution of trans 16:1 and 18:1 isomers ranged from 0.3% in the brain to 4.0% in adipose tissue, while trans 18:2 isomers ranged from 0.0% in the brain to 0.4% in adipose tissue. No trans 18:3 isomers were detected. Positional isomer ratios for cis 16:1 (delta 9 vs delta 7) and cis 18:1 (delta 11 vs delta 9) were also determined. Since these ratios are reproducible from one individual to the next, they might be useful for diagnosis of human metabolic disorders.

Adult soft tissue sarcomas: conventional therapies and molecularly targeted approaches.

PubMed

Mocellin, Simone; Rossi, Carlo R; Brandes, Alba; Nitti, Donato

2006-02-01

The therapeutic approach to soft tissue sarcomas (STS) has evolved over the past two decades based on the results from randomized controlled trials, which are guiding physicians in the treatment decision-making process. Despite significant improvements in the control of local disease, a significant number of patients ultimately die of recurrent/metastatic disease following radical surgery due to a lack of effective adjuvant treatments. In addition, the characteristic chemoresistance of STS has compromised the therapeutic value of conventional antineoplastic agents in cases of unresectable advanced/metastatic disease. Therefore, novel therapeutic strategies are urgently needed to improve the prognosis of patients with STS. Recent advances in STS biology are paving the way to the development of molecularly targeted therapeutic strategies, the efficacy of which relies not only on the knowledge of the molecular mechanisms underlying cancer development/progression but also on the personalization of the therapeutic regimen according to the molecular features of individual tumours. In this work, we review the state-of-the-art of conventional treatments for STS and summarize the most promising findings in the development of molecularly targeted therapeutic approaches.

Distribution of Interleukin-22-secreting Immune Cells in Conjunctival Associated Lymphoid Tissue.

PubMed

Yoon, Chang Ho; Lee, Daeseung; Jeong, Hyun Jeong; Ryu, Jin Suk; Kim, Mee Kum

2018-04-01

Interleukin (IL)-22 is a cytokine involved in epithelial cell regeneration. Currently, no research studies have analyzed the distribution of the three distinct IL-22-secreting cell populations in human or mouse conjunctiva. This study investigated the distribution of the three main populations of IL-22-secreting immune cells, αβ Th cells, γδ T cells, or innate cells (innate lymphoid cells [ILCs] or natural killer cells), in conjunctival associated lymphoid tissues (CALTs) in human and mouse models. We collected discarded cadaveric bulbar conjunctival tissue specimens after preservation of the corneo-limbal tissue for keratoplasty from four enucleated eyes of the domestic donor. The bulbar conjunctiva tissue, including the cornea from normal (n = 27) or abraded (n = 4) B6 mice, were excised and pooled in RPMI 1640 media. After the lymphoid cells were gated in forward and side scattering, the αβ Th cells, γδ T cells, or innate lymphoid cells were positively or negatively gated using anti-CD3, anti-γδ TCR, and anti-IL-22 antibodies, with a FACSCanto flow cytometer. In normal human conjunctiva, the percentage and number of cells were highest in αβ Th cells, followed by γδ T cells and CD3- γδ TCR- IL-22+ innate cells (presumed ILCs, pILCs) (Kruskal-Wallis test, p = 0.012). In normal mice keratoconjunctiva, the percentage and total number were highest in γδ T cells, followed by αβ Th cells and pILCs (Kruskal-Wallis test, p = 0.0004); in corneal abraded mice, the population of αβ Th cells and pILCs tended to increase. This study suggests that three distinctive populations of IL-22-secreting immune cells are present in CALTs of both humans and mice, and the proportions of IL-22+αβ Th cells, γδ T cells, and pILCs in CALTs in humans might be differently distributed from those in normal mice. © 2018 The Korean Ophthalmological Society.

Incorporation of lysosomal sequestration in the mechanistic model for prediction of tissue distribution of basic drugs.

PubMed

Assmus, Frauke; Houston, J Brian; Galetin, Aleksandra

2017-11-15

The prediction of tissue-to-plasma water partition coefficients (Kpu) from in vitro and in silico data using the tissue-composition based model (Rodgers & Rowland, J Pharm Sci. 2005, 94(6):1237-48.) is well established. However, distribution of basic drugs, in particular into lysosome-rich lung tissue, tends to be under-predicted by this approach. The aim of this study was to develop an extended mechanistic model for the prediction of Kpu which accounts for lysosomal sequestration and the contribution of different cell types in the tissue of interest. The extended model is based on compound-specific physicochemical properties and tissue composition data to describe drug ionization, distribution into tissue water and drug binding to neutral lipids, neutral phospholipids and acidic phospholipids in tissues, including lysosomes. Physiological data on the types of cells contributing to lung, kidney and liver, their lysosomal content and lysosomal pH were collated from the literature. The predictive power of the extended mechanistic model was evaluated using a dataset of 28 basic drugs (pK a ≥7.8, 17 β-blockers, 11 structurally diverse drugs) for which experimentally determined Kpu data in rat tissue have been reported. Accounting for the lysosomal sequestration in the extended mechanistic model improved the accuracy of Kpu predictions in lung compared to the original Rodgers model (56% drugs within 2-fold or 88% within 3-fold of observed values). Reduction in the extent of Kpu under-prediction was also evident in liver and kidney. However, consideration of lysosomal sequestration increased the occurrence of over-predictions, yielding overall comparable model performances for kidney and liver, with 68% and 54% of Kpu values within 2-fold error, respectively. High lysosomal concentration ratios relative to cytosol (>1000-fold) were predicted for the drugs investigated; the extent differed depending on the lysosomal pH and concentration of acidic phospholipids among

Targeting diseased tissues by pHLIP insertion at low cell surface pH.

PubMed

Andreev, Oleg A; Engelman, Donald M; Reshetnyak, Yana K

2014-01-01

The discovery of the pH Low Insertion Peptides (pHLIPs®) provides an opportunity to develop imaging and drug delivery agents targeting extracellular acidity. Extracellular acidity is associated with many pathological states, such as those in cancer, ischemic stroke, neurotrauma, infection, lacerations, and others. The metabolism of cells in injured or diseased tissues often results in the acidification of the extracellular environment, so acidosis might be useful as a general marker for the imaging and treatment of diseased states if an effective targeting method can be developed. The molecular mechanism of a pHLIP peptide is based on pH-dependent membrane-associated folding. pHLIPs, being moderately hydrophobic peptides, have high affinities for cellular membranes at normal pH, but fold and insert across membranes at low pH, allowing them to sense pH at the surfaces of cells in diseased tissues, where it is the lowest. Here we discuss the main principles of pHLIP interactions with membrane lipid bilayers at neutral and low pHs, the possibility of tuning the folding and insertion pH by peptide sequence variation, and potential applications of pHLIPs for imaging, therapy and image-guided interventions.

Tissue distribution and developmental expression of type XVI collagen in the mouse.

PubMed

Lai, C H; Chu, M L

1996-04-01

The expression of a recently identified collagen, alpha 1 (XVI), in adult mouse tissue and developing mouse embryo was examined by immunohistochemistry and in situ hybridization. A polyclonal antiserum was raised against a recombinant fusion protein, which contained a segment of 161 amino acids in the N-terminal noncollagenous domain of the human alpha 1 (XVI) collagen. Immunoprecipitation of metabolically labelled human or mouse fibroblast cell lysates with this antibody revealed a major, bacterial collagenase sensitive polypeptide of approximately 210 kDa. The size agrees with the prediction from the full-length cDNA. Immunofluorescence examination of adult mouse tissues using the affinity purified antibody revealed a rather broad distribution of the protein. The heart, kidney, intestine, ovary, testis, eye, arterial walls and smooth muscles all exhibited significant levels of expression, while the skeletal muscle, lung and brain showed very restricted and low signals. During development, no significant expression of the mRNA or protein was observed in embryo of day 8 of gestation, but strong signals was detected in placental trophoblasts. Expression in embryos was detectable first after day 11 of gestation with weak positive signals appearing in the heart. In later stages of development, stronger RNA hybridizations were observed in a variety of tissues, particularly in atrial and ventricular walls of the developing heart, spinal root neural fibers and skin. These data demonstrate that type XVI collagen represents another collagenous component widely distributed in the extracellular matrix and may contribute to the structural integrity of various tissues.

Whole-body tissue distribution of total radioactivity in rats after oral administration of [¹⁴C]-bilastine.

PubMed

Lucero, María Luisa; Patterson, Andrew B

2012-06-01

This study evaluated the tissue distribution of total radioactivity in male albino, male pigmented, and time-mated female albino rats after oral administration of a single dose of [¹⁴C]-bilastine (20 mg/kg). Although only 1 animal was analyzed at each time point, there were apparent differences in bilastine distribution. Radioactivity was distributed to only a few tissues at low levels in male rats, whereas distribution was more extensive and at higher levels in female rats. This may be a simple sex-related difference. In each group and at each time point, concentrations of radioactivity were high in the liver and kidney, reflecting the role of these organs in the elimination process. In male albino rats, no radioactivity was measurable by 72 hours postdose. In male pigmented rats, only the eye and uveal tract had measurable levels of radioactivity at 24 hours. Measureable levels of radioactivity were retained in these tissues at the final sampling time point (336 hours postdose), indicating a degree of melanin-associated binding. In time-mated female rats, but not in albino or pigmented male rats, there was evidence of low-level passage of radioactivity across the placental barrier into fetal tissues as well as low-level transfer of radioactivity into the brain.

Distribution of Hydroxychloroquine in Lymphoid Tissue in a Rabbit Model for HIV Infection

PubMed Central

González-Hernández, Iliana; Aguirre-Cruz, Lucinda; Sotelo, Julio; López-Arellano, Raquel; Morales-Hipólito, Adriana

2014-01-01

Hydroxychloroquine has been proposed for HIV treatment; however, little is known about its disposition in the lymphatic system, where replication takes place. Therefore, its distribution in lymphoid tissues (Peyer's patches and popliteal, submandibular, femoral, splenic, and prescapular lymph nodes) was evaluated and compared with that in blood. Results showed a high affinity of hydroxychloroquine for all of these tissues, with higher affinity for the splenic and submandibular lymph nodes, suggesting its potential use as a coadjuvant in HIV therapy. PMID:24145523

Mitomycin C dissolved in a reversible thermosetting gel: target tissue concentrations in the rabbit eye

PubMed Central

Ichien, K.; Yamamoto, T.; Kitazawa, Y.; Oguri, A.; Ando, H.; Kondo, Y.

1997-01-01

AIMS—To determine whether a new, reversible thermosetting gel enhances mitomycin C transfer to target ocular tissues in the rabbit eye.
METHODS—A 0.1 ml solution of mitomycin C containing 0.22 µg, 2.9 µg, or 28 µg of the agent dissolved in a reversible thermosetting gel consisting of methylcellulose, citric acid, and polyethylene glycol was injected subconjunctivally in 30 New Zealand albino rabbits. Scleral and conjunctival tissues were excised at 0.5, 1, 2, 4, or 24 hours after the injection and mitomycin C concentrations in these tissues were determined by high performance liquid chromatography. The concentration over time was approximated to a single exponential curve, and initial mitomycin C concentrations, time constants, and half life values were determined. Finally, the areas under the curves (AUCs) between 0.5 and 24 hours were calculated.
RESULTS—The mitomycin C concentrations in the target tissues were dose dependent and decreased rapidly over 24 hours. Both the initial mitomycin C concentrations as well as AUCs in these eyes treated with mitomycin C, dissolved in a reversible thermosetting gel, were higher than those in eyes treated similarly in a previous study in which the gel was not used.
CONCLUSION—Applied subconjunctivally in the rabbit eye, mitomycin C dissolved in the reversible thermosetting gel enhanced transfer of the agent to the sclera and the conjunctiva.

 PMID:9135413

The Research Progress of Targeted Drug Delivery Systems

NASA Astrophysics Data System (ADS)

Zhan, Jiayin; Ting, Xizi Liang; Zhu, Junjie

2017-06-01

Targeted drug delivery system (DDS) means to selectively transport drugs to targeted tissues, organs, and cells through a variety of drugs carrier. It is usually designed to improve the pharmacological and therapeutic properties of conventional drugs and to overcome problems such as limited solubility, drug aggregation, poor bio distribution and lack of selectivity, controlling drug release carrier and to reduce normal tissue damage. With the characteristics of nontoxic and biodegradable, it can increase the retention of drug in lesion site and the permeability, improve the concentration of the drug in lesion site. at present, there are some kinds of DDS using at test phase, such as slow controlled release drug delivery system, targeted drug delivery systems, transdermal drug delivery system, adhesion dosing system and so on. This paper makes a review for DDS.

Interrogating the relationship between rat in vivo tissue distribution and drug property data for >200 structurally unrelated molecules

PubMed Central

Harrell, Andrew W; Sychterz, Caroline; Ho, May Y; Weber, Andrew; Valko, Klara; Negash, Kitaw

2015-01-01

The ability to explain distribution patterns from drug physicochemical properties and binding characteristics has been explored for more than 200 compounds by interrogating data from quantitative whole body autoradiography studies (QWBA). These in vivo outcomes have been compared to in silico and in vitro drug property data to determine the most influential properties governing drug distribution. Consistent with current knowledge, in vivo distribution was most influenced by ionization state and lipophilicity which in turn affected phospholipid and plasma protein binding. Basic and neutral molecules were generally better distributed than acidic counterparts demonstrating weaker plasma protein and stronger phospholipid binding. The influence of phospholipid binding was particularly evident in tissues with high phospholipid content like spleen and lung. Conversely, poorer distribution of acidic drugs was associated with stronger plasma protein and weaker phospholipid binding. The distribution of a proportion of acidic drugs was enhanced, however, in tissues known to express anionic uptake transporters such as the liver and kidney. Greatest distribution was observed into melanin containing tissues of the eye, most likely due to melanin binding. Basic molecules were consistently better distributed into parts of the eye and skin containing melanin than those without. The data, therefore, suggest that drug binding to macromolecules strongly influences the distribution of total drug for a large proportion of molecules in most tissues. Reducing lipophilicity, a strategy often used in discovery to optimize pharmacokinetic properties such as absorption and clearance, also decreased the influence of nonspecific binding on drug distribution. PMID:26516585

Targeting the NO/superoxide ratio in adipose tissue: relevance to obesity and diabetes management.

PubMed

Jankovic, Aleksandra; Korac, Aleksandra; Buzadzic, Biljana; Stancic, Ana; Otasevic, Vesna; Ferdinandy, Péter; Daiber, Andreas; Korac, Bato

2017-06-01

Insulin sensitivity and metabolic homeostasis depend on the capacity of adipose tissue to take up and utilize excess glucose and fatty acids. The key aspects that determine the fuel-buffering capacity of adipose tissue depend on the physiological levels of the small redox molecule, nitric oxide (NO). In addition to impairment of NO synthesis, excessive formation of the superoxide anion (О 2 •- ) in adipose tissue may be an important interfering factor diverting the signalling of NO and other reactive oxygen and nitrogen species in obesity, resulting in metabolic dysfunction of adipose tissue over time. Besides its role in relief from superoxide burst, enhanced NO signalling may be responsible for the therapeutic benefits of different superoxide dismutase mimetics, in obesity and experimental diabetes models. This review summarizes the role of NO in adipose tissue and highlights the effects of NO/О 2 •- ratio 'teetering' as a promising pharmacological target in the metabolic syndrome. This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc. © 2016 The British Pharmacological Society.

Estimating oxygen distribution from vasculature in three-dimensional tumour tissue.

PubMed

Grimes, David Robert; Kannan, Pavitra; Warren, Daniel R; Markelc, Bostjan; Bates, Russell; Muschel, Ruth; Partridge, Mike

2016-03-01

Regions of tissue which are well oxygenated respond better to radiotherapy than hypoxic regions by up to a factor of three. If these volumes could be accurately estimated, then it might be possible to selectively boost dose to radio-resistant regions, a concept known as dose-painting. While imaging modalities such as 18F-fluoromisonidazole positron emission tomography (PET) allow identification of hypoxic regions, they are intrinsically limited by the physics of such systems to the millimetre domain, whereas tumour oxygenation is known to vary over a micrometre scale. Mathematical modelling of microscopic tumour oxygen distribution therefore has the potential to complement and enhance macroscopic information derived from PET. In this work, we develop a general method of estimating oxygen distribution in three dimensions from a source vessel map. The method is applied analytically to line sources and quasi-linear idealized line source maps, and also applied to full three-dimensional vessel distributions through a kernel method and compared with oxygen distribution in tumour sections. The model outlined is flexible and stable, and can readily be applied to estimating likely microscopic oxygen distribution from any source geometry. We also investigate the problem of reconstructing three-dimensional oxygen maps from histological and confocal two-dimensional sections, concluding that two-dimensional histological sections are generally inadequate representations of the three-dimensional oxygen distribution. © 2016 The Authors.

Estimating oxygen distribution from vasculature in three-dimensional tumour tissue

PubMed Central

Kannan, Pavitra; Warren, Daniel R.; Markelc, Bostjan; Bates, Russell; Muschel, Ruth; Partridge, Mike

2016-01-01

Regions of tissue which are well oxygenated respond better to radiotherapy than hypoxic regions by up to a factor of three. If these volumes could be accurately estimated, then it might be possible to selectively boost dose to radio-resistant regions, a concept known as dose-painting. While imaging modalities such as 18F-fluoromisonidazole positron emission tomography (PET) allow identification of hypoxic regions, they are intrinsically limited by the physics of such systems to the millimetre domain, whereas tumour oxygenation is known to vary over a micrometre scale. Mathematical modelling of microscopic tumour oxygen distribution therefore has the potential to complement and enhance macroscopic information derived from PET. In this work, we develop a general method of estimating oxygen distribution in three dimensions from a source vessel map. The method is applied analytically to line sources and quasi-linear idealized line source maps, and also applied to full three-dimensional vessel distributions through a kernel method and compared with oxygen distribution in tumour sections. The model outlined is flexible and stable, and can readily be applied to estimating likely microscopic oxygen distribution from any source geometry. We also investigate the problem of reconstructing three-dimensional oxygen maps from histological and confocal two-dimensional sections, concluding that two-dimensional histological sections are generally inadequate representations of the three-dimensional oxygen distribution. PMID:26935806

Tissue distribution and functional analysis of vitellogenin-6 of Toxocara canis.

PubMed

Zhu, Hong-Hong; Ma, Guang-Xu; Luo, Yong-Fang; Luo, Yong-Li; Yin, Sha-Sha; Xiong, Yi; Zhou, Rong-Qiong

2017-06-01

Toxocara canis is an common intestinal nematode of canids and the principal causative agent of human toxocariasis. Vitellogenin (Vg), a source of amino acids and lipids in the eggs, are considered to play an important role in embryo development of a wide range of organisms. In the present study, the transcriptional levels of Tc-vit-6 gene in male and female adult T. canis were determined by quantitative real-time PCR, which indicated high transcription of Tc-vit-6 in the intestine, reproductive tract and body wall of male and female adult T. canis. The fragment of Tc-vit-6 encoding a vWD domain, was cloned and expressed to produce a rabbit anti-TcvWD polyclonal antibody. Tissue distribution of TcVg6 was detected by immunohistochemical assays, which showed predominant distribution of TcVg6 in the tissues of intestine, as well as reproductive tract (including some of the germ cells) and musculature of male and female adult worms. Collectively, these results indicated multiple biological roles of TcVg6 apart from that in the reproduction of T. canis. Copyright © 2017 Elsevier Inc. All rights reserved.

Distributed ISAR Subimage Fusion of Nonuniform Rotating Target Based on Matching Fourier Transform.

PubMed

Li, Yuanyuan; Fu, Yaowen; Zhang, Wenpeng

2018-06-04

In real applications, the image quality of the conventional monostatic Inverse Synthetic Aperture Radar (ISAR) for the maneuvering target is subject to the strong fluctuation of Radar Cross Section (RCS), as the target aspect varies enormously. Meanwhile, the maneuvering target introduces nonuniform rotation after translation motion compensation which degrades the imaging performance of the conventional Fourier Transform (FT)-based method in the cross-range dimension. In this paper, a method which combines the distributed ISAR technique and the Matching Fourier Transform (MFT) is proposed to overcome these problems. Firstly, according to the characteristics of the distributed ISAR, the multiple channel echoes of the nonuniform rotation target from different observation angles can be acquired. Then, by applying the MFT to the echo of each channel, the defocused problem of nonuniform rotation target which is inevitable by using the FT-based imaging method can be avoided. Finally, after preprocessing, scaling and rotation of all subimages, the noncoherent fusion image containing all the RCS information in all channels can be obtained. The accumulation coefficients of all subimages are calculated adaptively according to the their image qualities. Simulation and experimental data are used to validate the effectiveness of the proposed approach, and fusion image with improved recognizability can be obtained. Therefore, by using the distributed ISAR technique and MFT, subimages of high-maneuvering target from different observation angles can be obtained. Meanwhile, by employing the adaptive subimage fusion method, the RCS fluctuation can be alleviated and more recognizable final image can be obtained.

Magnetic nanoparticle-based approaches to locally target therapy and enhance tissue regeneration in vivo.

PubMed

Sensenig, Richard; Sapir, Yulia; MacDonald, Cristin; Cohen, Smadar; Polyak, Boris

2012-09-01

Magnetic-based systems utilizing superparamagnetic nanoparticles and a magnetic field gradient to exert a force on these particles have been used in a wide range of biomedical applications. This review is focused on drug targeting applications that require penetration of a cellular barrier as well as strategies to improve the efficacy of targeting in these biomedical applications. Another focus of this review is regenerative applications utilizing tissue engineered scaffolds prepared with the aid of magnetic particles, the use of remote actuation for release of bioactive molecules and magneto-mechanical cell stimulation, cell seeding and cell patterning.

Magnetic nanoparticle-based approaches to locally target therapy and enhance tissue regeneration in vivo

PubMed Central

Sensenig, Richard; Sapir, Yulia; MacDonald, Cristin; Cohen, Smadar; Polyak, Boris

2013-01-01

Magnetic-based systems utilizing superparamagnetic nanoparticles and a magnetic field gradient to exert a force on these particles have been used in a wide range of biomedical applications. This review is focused on drug targeting applications that require penetration of a cellular barrier as well as strategies to improve the efficacy of targeting in these biomedical applications. Another focus of this review is regenerative applications utilizing tissue engineered scaffolds prepared with the aid of magnetic particles, the use of remote actuation for release of bioactive molecules and magneto–mechanical cell stimulation, cell seeding and cell patterning. PMID:22994959

Scan statistics with local vote for target detection in distributed system

NASA Astrophysics Data System (ADS)

Luo, Junhai; Wu, Qi

2017-12-01

Target detection has occupied a pivotal position in distributed system. Scan statistics, as one of the most efficient detection methods, has been applied to a variety of anomaly detection problems and significantly improves the probability of detection. However, scan statistics cannot achieve the expected performance when the noise intensity is strong, or the signal emitted by the target is weak. The local vote algorithm can also achieve higher target detection rate. After the local vote, the counting rule is always adopted for decision fusion. The counting rule does not use the information about the contiguity of sensors but takes all sensors' data into consideration, which makes the result undesirable. In this paper, we propose a scan statistics with local vote (SSLV) method. This method combines scan statistics with local vote decision. Before scan statistics, each sensor executes local vote decision according to the data of its neighbors and its own. By combining the advantages of both, our method can obtain higher detection rate in low signal-to-noise ratio environment than the scan statistics. After the local vote decision, the distribution of sensors which have detected the target becomes more intensive. To make full use of local vote decision, we introduce a variable-step-parameter for the SSLV. It significantly shortens the scan period especially when the target is absent. Analysis and simulations are presented to demonstrate the performance of our method.

Small and intermediate conductance Ca(2+)-activated K+ channels confer distinctive patterns of distribution in human tissues and differential cellular localisation in the colon and corpus cavernosum.

PubMed

Chen, Mao Xiang; Gorman, Shelby A; Benson, Bill; Singh, Kuljit; Hieble, J Paul; Michel, Martin C; Tate, Simon N; Trezise, Derek J

2004-06-01

The SK/IK family of small and intermediate conductance calcium-activated potassium channels contains four members, SK1, SK2, SK3 and IK1, and is important for the regulation of a variety of neuronal and non-neuronal functions. In this study we have analysed the distribution of these channels in human tissues and their cellular localisation in samples of colon and corpus cavernosum. SK1 mRNA was detected almost exclusively in neuronal tissues. SK2 mRNA distribution was restricted but more widespread than SK1, and was detected in adrenal gland, brain, prostate, bladder, liver and heart. SK3 mRNA was detected in almost every tissue examined. It was highly expressed in brain and in smooth muscle-rich tissues including the clitoris and the corpus cavernosum, and expression in the corpus cavernosum was upregulated up to 5-fold in patients undergoing sex-change operations. IK1 mRNA was present in surface-rich, secretory and inflammatory cell-rich tissues, highest in the trachea, prostate, placenta and salivary glands. In detailed immunohistochemical studies of the colon and the corpus cavernosum, SK1-like immunoreactivity was observed in the enteric neurons. SK3-like immunoreactivity was observed strongly in smooth muscle and vascular endothelium. IK1-like immunoreactivity was mainly observed in inflammatory cells and enteric neurons of the colon, but absent in corpus cavernosum. These distinctive patterns of distribution suggest that these channels are likely to have different biological functions and could be specifically targeted for a number of human diseases, such as irritable bowel syndrome, hypertension and erectile dysfunction.

Pharmacokinetics and metabolism of benzene in Zymbal gland and other key target tissues after oral administration in rats.

PubMed Central

Low, L K; Meeks, J R; Norris, K J; Mehlman, M A; Mackerer, C R

1989-01-01

Solid tumors have been reported in the Zymbal gland, oral and nasal cavities, and mammary gland of Sprague-Dawley rats following chronic oral administration of benzene. The cause for the specificity of such lesions remains unclear, but it is possible that tissue-specific metabolism or pharmacokinetics of benzene is responsible. Metabolism and pharmacokinetic studies were carried out in our laboratory with 14C-benzene at oral doses of 0.15 to 500 mg/kg to ascertain tissue retention, metabolite profile, and elimination kinetics in target and nontarget organs and in blood. Findings from those studies indicate the following: a) the Zymbal gland is not a sink or a site of accumulation for benzene or its metabolites even after a single high dose (500 mg/kg) or after repeated oral administration; b) the metabolite profile is quantitatively different in target tissues (e.g., Zymbal gland, nasal cavity), nontarget tissues and blood; and (c) pharmacokinetic studies show that the elimination of radioactivity from the Zymbal gland is biphasic. PMID:2792043

In situ localization and tissue distribution of ostreid herpesvirus 1 proteins in infected Pacific oyster, Crassostrea gigas.

PubMed

Martenot, Claire; Segarra, Amélie; Baillon, Laury; Faury, Nicole; Houssin, Maryline; Renault, Tristan

2016-05-01

Immunohistochemistry (IHC) assays were conducted on paraffin sections from experimentally infected spat and unchallenged spat produced in hatchery to determine the tissue distribution of three viral proteins within the Pacific oyster, Crassostrea gigas. Polyclonal antibodies were produced from recombinant proteins corresponding to two putative membrane proteins and one putative apoptosis inhibitor encoded by ORF 25, 72, and 87, respectively. Results were then compared to those obtained by in situ hybridization performed on the same individuals, and showed a substantial agreement according to Landis and Koch numeric scale. Positive signals were mainly observed in connective tissue of gills, mantle, adductor muscle, heart, digestive gland, labial palps, and gonads of infected spat. Positive signals were also reported in digestive epithelia. However, few positive signals were also observed in healthy appearing oysters (unchallenged spat) and could be due to virus persistence after a primary infection. Cellular localization of staining seemed to be linked to the function of the viral protein targeted. A nucleus staining was preferentially observed with antibodies targeting the putative apoptosis inhibitor protein whereas a cytoplasmic localization was obtained using antibodies recognizing putative membrane proteins. The detection of viral proteins was often associated with histopathological changes previously reported during OsHV-1 infection by histology and transmission electron microscopy. Within the 6h after viral suspension injection, positive signals were almost at the maximal level with the three antibodies and all studied organs appeared infected at 28h post viral injection. Connective tissue appeared to be a privileged site for OsHV-1 replication even if positive signals were observed in the epithelium cells of different organs which may be interpreted as a hypothetical portal of entry or release for the virus. IHC constitutes a suited method for analyzing the

Tissue distribution and depuration kinetics of waterborne 14C-labeled light PAHs in mummichog (Fundulus heteroclitus).

PubMed

Valdez Domingos, F X; Oliveira Ribeiro, C A; Pelletier, É; Rouleau, C

2011-04-01

Light polycyclic aromatic hydrocarbons (PAHs) of petrogenic origin are commonly found in estuaries and coastal areas. Though they are known to be toxic to fish, little is known about their uptake and tissue distribution. This paper reports on the results of a study on uptake, elimination, and tissue distribution of three waterborne 14C-labeled PAHs in the mummichog, Fundulus heteroclitus, using whole-body autoradiography. After a 24 h exposure to 1 μCi·L(-1) of 14C-naphthalene, 14C-1-naphthol, and 14C-phenanthrene, fish were transferred to clean water and tissue distribution examined after 0, 1, 3, 7, 14, and 21 days of depuration. All compounds were readily accumulated by fish and were also rapidly eliminated (t0.5 range=1.1 to 3.0 days). Most of the radioactivity in naphthalene- and phenanthrene-treated fish was found in gall bladder≫liver>intestinal lumen. In naphthol-exposed fish, an important labeling of some brain areas was observed. Brain of naphthalene-exposed fish was also labeled after 24 h depuration, indicating that exposure to naphthalene may result in metabolite accumulation in the brain. This is the first study showing that naphthalene, naphthol, and/or unidentified metabolite(s) can accumulate in brain tissues, which may impair normal brain function.

Distribution and accumulation of rotenone in tissues of warm water fishes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rach, J.J.; Gingerich, W.H.

1986-03-01

The tissue distribution of rotenoid residues was determined in tissues of common carp Cyprinus carpio (88.2 g), bluegills Lepomis macrochirus (47.9 g), and yellow perch Perca flavescens (67.7 g) after the fish were exposed to 50..mu..g/L of rotenone-6a/sup 14/C(15.9 x 10/sup 4/ Bq/..mu..M). Exposures were terminated 1 h after the fish were moribund and failed to respond to gentle prodding. The fish were dissected, and various tissues were oxidized to determine /sup 14/C-rotenone accumulation and distribution. Major rotenone metabolites were identified by gradient-elution high performance liquid chromatography. The exposure time required for fish to reach total incapacitation was 3 hmore » for bluegills and yellow perch, and 11.25 h for common carp. The mean rotenoid concentrations (..mu..g/100g fish) in the whole body were 22.4 in yellow perch, 39.7 in bluegills, and 107.8 in common carp. The percentage of rotenone-derived /sup 14/C activity was higher in the carcass components than in the head or viscera; the skin and bone contained about 60% of the carcass activity. The highest relative rotenoid concentrations were found in the liver, bile, gills, brain, and heart. Percentages of total rotenoid material as parent rotenone were highest in yellow perch (70.0 in the viscera and 84.4 in the fillet), followed by those for bluegills (22.7 and 27.8) and common carp (9.7 and 48.5).« less

Moving target tracking through distributed clustering in directional sensor networks.

PubMed

Enayet, Asma; Razzaque, Md Abdur; Hassan, Mohammad Mehedi; Almogren, Ahmad; Alamri, Atif

2014-12-18

The problem of moving target tracking in directional sensor networks (DSNs) introduces new research challenges, including optimal selection of sensing and communication sectors of the directional sensor nodes, determination of the precise location of the target and an energy-efficient data collection mechanism. Existing solutions allow individual sensor nodes to detect the target's location through collaboration among neighboring nodes, where most of the sensors are activated and communicate with the sink. Therefore, they incur much overhead, loss of energy and reduced target tracking accuracy. In this paper, we have proposed a clustering algorithm, where distributed cluster heads coordinate their member nodes in optimizing the active sensing and communication directions of the nodes, precisely determining the target location by aggregating reported sensing data from multiple nodes and transferring the resultant location information to the sink. Thus, the proposed target tracking mechanism minimizes the sensing redundancy and maximizes the number of sleeping nodes in the network. We have also investigated the dynamic approach of activating sleeping nodes on-demand so that the moving target tracking accuracy can be enhanced while maximizing the network lifetime. We have carried out our extensive simulations in ns-3, and the results show that the proposed mechanism achieves higher performance compared to the state-of-the-art works.

Moving Target Tracking through Distributed Clustering in Directional Sensor Networks

PubMed Central

Enayet, Asma; Razzaque, Md. Abdur; Hassan, Mohammad Mehedi; Almogren, Ahmad; Alamri, Atif

2014-01-01

The problem of moving target tracking in directional sensor networks (DSNs) introduces new research challenges, including optimal selection of sensing and communication sectors of the directional sensor nodes, determination of the precise location of the target and an energy-efficient data collection mechanism. Existing solutions allow individual sensor nodes to detect the target's location through collaboration among neighboring nodes, where most of the sensors are activated and communicate with the sink. Therefore, they incur much overhead, loss of energy and reduced target tracking accuracy. In this paper, we have proposed a clustering algorithm, where distributed cluster heads coordinate their member nodes in optimizing the active sensing and communication directions of the nodes, precisely determining the target location by aggregating reported sensing data from multiple nodes and transferring the resultant location information to the sink. Thus, the proposed target tracking mechanism minimizes the sensing redundancy and maximizes the number of sleeping nodes in the network. We have also investigated the dynamic approach of activating sleeping nodes on-demand so that the moving target tracking accuracy can be enhanced while maximizing the network lifetime. We have carried out our extensive simulations in ns-3, and the results show that the proposed mechanism achieves higher performance compared to the state-of-the-art works. PMID:25529205

Distribution of OV-TL 3 and MOv18 in normal and malignant ovarian tissue.

PubMed

Buist, M R; Molthoff, C F; Kenemans, P; Meijer, C J

1995-07-01

To analyse the distribution of OV-TL 3 and MOv18 in normal ovarian tissue to determine which antibody is most suitable for (radio)immunotherapy of ovarian carcinoma. The distribution of OV-TL 3 and MOv18 was determined using immunohistochemistry and flow cytometry. Epithelial and other cells in many tissues, and leucocytes in peripheral blood, bone marrow and spleen stained positively with OV-TL 3. The staining pattern of MOv18 in normal tissues was more restricted and was confined to epithelial cells in the lung, kidney, pancreas, salivary gland, ovary, Fallopian tubes, and cervix. Reactivity was also observed with pneumocytes in the lung, tubuli in the kidney, acinar cells in the salivary gland and pancreas, in the placenta, and with Kupffer cells in the liver. The staining pattern of chimeric MOv18 was identical with the murine form. OV-TL 3 and MOv18 reacted with 100% and 98% (45/46) of the 46 tested epithelial ovarian cancers, respectively. In ovarian carcinoma tissue homogeneous staining of epithelial cells was observed with OV-TL 3 and more heterogeneous staining with MOv18. In 12 and nine patients, respectively, a difference in staining intensity for OV-TL 3 and MOv18 was observed between various tumour samples from the same patient. MOv18 has greater therapeutic potential because of its restricted reactivity with normal tissues and especially, in contrast to OV-TL 3, its lack of reactivity with haematopoietic cells.

Near infrared spectral polarization imaging of prostate cancer tissues using Cybesin: a receptor-targeted contrast agent

NASA Astrophysics Data System (ADS)

Pu, Yang; Wang, W. B.; Tang, G. C.; Liang, Kexian; Achilefu, S.; Alfano, R. R.

2013-03-01

Cybesin, a smart contrast agent to target cancer cells, was investigated using a near infrared (NIR) spectral polarization imaging technique for prostate cancer detection. The approach relies on applying a contrast agent that can target cancer cells. Cybesin, as a small ICG-derivative dye-peptide, emit fluorescence between 750 nm and 900 nm, which is in the "tissue optical window". Cybesin was reported targeting the over-expressed bombesin receptors in cancer cells in animal model and the human prostate cancers over-expressing bombesin receptors. The NIR spectral polarization imaging study reported here demonstrated that Cybesin can be used as a smart optical biomarker and as a prostate cancer receptor targeted contrast agent.

Ejecta velocity distribution for impact cratering experiments on porous and low strength targets

NASA Astrophysics Data System (ADS)

Michikami, Tatsuhiro; Moriguchi, Kouichi; Hasegawa, Sunao; Fujiwara, Akira

2007-01-01

Impact cratering experiments on porous targets with various compressive strength ranging from ˜0.5 to ˜250 MPa were carried out in order to investigate the relationship between the ejecta velocity, and material strength or porosity of the target. A spherical alumina projectile (diameter ˜1 mm) was shot perpendicularly into the target surface with velocity ranging from 1.2 to 4.5 km/s (nominal 4 km/s), using a two-stage light-gas gun. The ejecta velocity was estimated from the fall point distance of ejecta. The results show that there are in fact a large fraction of ejecta with very low velocities when the material strength of the target is small and the porosity is high. As an example, in the case of one specific target (compressive strength ˜0.5 MPa and porosity 43%), the amount of ejecta with velocities lower than 1 m/s is about 40% of the total mass. The average velocity of the ejecta decreases with decreasing material strength or increasing the porosity of the target. Moreover, in our experiments, the ejecta velocity distributions normalized to total ejecta mass seem to be mainly dependent on the material strength of the target, and not so greatly on the porosity. We also compare our experimental results with those of Gault et al. [1963. Spray ejected from the lunar surface by meteoroid impact. NASA Technical Note D-1767] and Housen [1992. Crater ejecta velocities for impacts on rocky bodies. LPSC XXIII, 555-556] for the ejecta velocity distribution using Housen's nondimensional scaling parameter. The ejecta velocity distributions of our experiments are lower than those of Gault et al. [1963. Spray ejected from the lunar surface by meteoroid impact. NASA Technical Note D-1767] and Housen [1992. Crater ejecta velocities for impacts on rocky bodies. LPSC XIII, 555-556].

The role of experience in location estimation: Target distributions shift location memory biases.

PubMed

Lipinski, John; Simmering, Vanessa R; Johnson, Jeffrey S; Spencer, John P

2010-04-01

Research based on the Category Adjustment model concluded that the spatial distribution of target locations does not influence location estimation responses [Huttenlocher, J., Hedges, L., Corrigan, B., & Crawford, L. E. (2004). Spatial categories and the estimation of location. Cognition, 93, 75-97]. This conflicts with earlier results showing that location estimation is biased relative to the spatial distribution of targets [Spencer, J. P., & Hund, A. M. (2002). Prototypes and particulars: Geometric and experience-dependent spatial categories. Journal of Experimental Psychology: General, 131, 16-37]. Here, we resolve this controversy by using a task based on Huttenlocher et al. (Experiment 4) with minor modifications to enhance our ability to detect experience-dependent effects. Results after the first block of trials replicate the pattern reported in Huttenlocher et al. After additional experience, however, participants showed biases that significantly shifted according to the target distributions. These results are consistent with the Dynamic Field Theory, an alternative theory of spatial cognition that integrates long-term memory traces across trials relative to the perceived structure of the task space. Copyright 2009 Elsevier B.V. All rights reserved.

Systemic distribution, subcellular localization and differential expression of sphingosine-1-phosphate receptors in benign and malignant human tissues

PubMed Central

Wang, Chunyi; Mao, Jinghe; Redfield, Samantha; Mo, Yinyuan; Lage, Janice M.; Zhou, Xinchun

2014-01-01

Aims Five sphingosine-1-phosphate receptors (S1PR): S1PR1, S1PR2, S1PR3, S1PR4 and S1PR5 (S1PR1-5) have been shown to be involved in the proliferation and progression of various cancers. However, none of the S1PRs have been systemically investigated. In this study, we performed immunohistochemistry (IHC) for S1PR1-S1PR5 on different tissues, in order to simultaneously determine the systemic distribution, subcellular localization and expression level of all five S1PRs. Methods We constructed tissue microarrays (TMAs) from 384 formalin-fixed paraffin-embedded (FFPE) blocks containing 183 benign and 201 malignant tissues from 34 human organs/systems. Then we performed IHC for all five S1PRs simultaneously on these TMA slides. The distribution, subcellular localization and expression of each S1PR were determined for each tissue. The data were then compared in benign and malignant tissues from the same organ/tissue using the student t-test. In order to reconfirm the subcellular localization of each S1PR as determined by IHC, immunocytochemistry (ICC) was performed on several malignant cell lines. Results We found that all five S1PRs are widely distributed in multiple human organs/systems. All S1PRs are expressed in both the cytoplasm and nucleus, except S1PR3, whose IHC signals are only seen in the nucleus. Interestingly, the S1PRs are rarely expressed on cellular membranes. Each S1PR is unique in its organ distribution, subcellular localization and expression level in benign and malignant tissues. Among the five S1PRs, S1PR5 has the highest expression level (either in nucleus or cytoplasm), with S1PR1, 3, 2 and 4 following in descending order. Strong nuclear expression was seen for S1PR1, S1PR3 and S1PR5, whereas S1PR2 and S1PR4 show only weak staining. Four organs/tissues (adrenal gland, liver, brain and colon) show significant differences in IHC scores for the multiple S1PRs (nuclear and/or cytoplasmic), nine (stomach, lymphoid tissues, lung, ovary, cervix, pancreas

Chemopreventive glucosinolate accumulation in various broccoli and collard tissues: Microfluidic-based targeted transcriptomics for by-product valorization

PubMed Central

Becker, Talon M.; Juvik, John A.

2017-01-01

Floret, leaf, and root tissues were harvested from broccoli and collard cultivars and extracted to determine their glucosinolate and hydrolysis product profiles using high performance liquid chromatography and gas chromotography. Quinone reductase inducing bioactivity, an estimate of anti-cancer chemopreventive potential, of the extracts was measured using a hepa1c1c7 murine cell line. Extracts from root tissues were significantly different from other tissues and contained high levels of gluconasturtiin and glucoerucin. Targeted gene expression analysis on glucosinolate biosynthesis revealed that broccoli root tissue has elevated gene expression of AOP2 and low expression of FMOGS-OX homologs, essentially the opposite of what was observed in broccoli florets, which accumulated high levels of glucoraphanin. Broccoli floret tissue has significantly higher nitrile formation (%) and epithionitrile specifier protein gene expression than other tissues. This study provides basic information of the glucosinolate metabolome and transcriptome for various tissues of Brassica oleracea that maybe utilized as potential byproducts for the nutraceutical market. PMID:28945821

Chemopreventive glucosinolate accumulation in various broccoli and collard tissues: Microfluidic-based targeted transcriptomics for by-product valorization.

PubMed

Lee, Young-Sang; Ku, Kang-Mo; Becker, Talon M; Juvik, John A

2017-01-01

Floret, leaf, and root tissues were harvested from broccoli and collard cultivars and extracted to determine their glucosinolate and hydrolysis product profiles using high performance liquid chromatography and gas chromotography. Quinone reductase inducing bioactivity, an estimate of anti-cancer chemopreventive potential, of the extracts was measured using a hepa1c1c7 murine cell line. Extracts from root tissues were significantly different from other tissues and contained high levels of gluconasturtiin and glucoerucin. Targeted gene expression analysis on glucosinolate biosynthesis revealed that broccoli root tissue has elevated gene expression of AOP2 and low expression of FMOGS-OX homologs, essentially the opposite of what was observed in broccoli florets, which accumulated high levels of glucoraphanin. Broccoli floret tissue has significantly higher nitrile formation (%) and epithionitrile specifier protein gene expression than other tissues. This study provides basic information of the glucosinolate metabolome and transcriptome for various tissues of Brassica oleracea that maybe utilized as potential byproducts for the nutraceutical market.

Distribution of Potato virus Y in potato plant organs, tissues, and cells.

PubMed

Kogovšek, P; Kladnik, A; Mlakar, J; Znidarič, M Tušek; Dermastia, M; Ravnikar, M; Pompe-Novak, M

2011-11-01

The distribution of Potato virus Y (PVY) in the systemically infected potato (Solanum tuberosum) plants of the highly susceptible cultivar Igor was investigated. Virus presence and accumulation was analyzed in different plant organs and tissues using real-time polymerase chain reaction and transmission electron microscopy (TEM) negative staining methods. To get a complete insight into the location of viral RNA within the tissue, in situ hybridization was developed and optimized for the detection of PVY RNA at the cellular level. PVY was shown to accumulate in all studied leaf and stem tissues, in shoot tips, roots, and tubers; however, the level of virus accumulation was specific for each organ or tissue. The highest amounts of viral RNA and viral particles were found in symptomatic leaves and stem. By observing cell ultrastructure with TEM, viral cytoplasmic inclusion bodies were localized in close vicinity to the epidermis and in trichomes. Our results show that viral RNA, viral particles, and cytoplasmic inclusion bodies colocalize within the same type of cells or in close vicinity.

Tissue distribution of molidone in a multidrug overdose.

PubMed

Flammia, Dwight D; Bateman, Henry R; Saady, Joseph J; Christensen, Erik D

2004-09-01

Molindone hydrochloride (Moban) is a dihydroindolone compound dissimilar in structure to other antipsychotic drugs (i.e., phenothiazines, butyrophenones, dibenzepines, and thioxanthenes). The antipsychotic (or neuroleptic) activity of molindone makes it particularly useful in the treatment of schizophrenia. There are a few published cases which report the tissue distribution of molindone in the human body. We report the analysis of molindone in postmortem samples using a solvent mixture (toluene/hexane/isoamyl alcohol) base extract followed by an acid (0.5M H(2)SO(4)) wash. Molindone was identified by gas chromatography-mass spectrometry (m/z 100, 176, 276) and quantitated using a gas chromatograph and nitrogen-phosphorus detector. The range of linearity was 0.1 mg/L to 5.0 mg/L. We report our findings of molindone concentrations in blood, liver, bile, gastric, and urine as follows: 6 mg/L in blood; 26 mg/kg in liver; 23.1 mg/L in bile; 1200 mg/L in gastric; and 37.3 mg/L in urine. Vitreous lithium (5.9 mmol/L) was determined by flame atomic absorption spectrometry. The medical examiner listed the cause of death as a combined drug overdose of molindone and lithium. The tissue results are compared with another case and the pharmacology of molindone is presented.

Dual targeting luminescent gold nanoclusters for tumor imaging and deep tissue therapy.

PubMed

Chen, Dan; Li, Bowen; Cai, Songhua; Wang, Peng; Peng, Shuwen; Sheng, Yuanzhi; He, Yuanyuan; Gu, Yueqing; Chen, Haiyan

2016-09-01

Dual targeting towards both extracellular and intracellular receptors specific to tumor is a significant approach for cancer diagnosis and therapy. In the present study, a novel nano-platform (AuNC-cRGD-Apt) with dual targeting function was initially established by conjugating gold nanocluster (AuNC) with cyclic RGD (cRGD) that is specific to αvβ3integrins over-expressed on the surface of tumor tissues and aptamer AS1411 (Apt) that is of high affinity to nucleolin over-expressed in the cytoplasm and nucleus of tumor cells. Then, AuNC-cRGD-Apt was further functionalized with near infrared (NIR) fluorescence dye (MPA), giving a NIR fluorescent dual-targeting probe AuNC-MPA-cRGD-Apt. AuNC-MPA-cRGD-Apt displays low cytotoxicity and favorable tumor-targeting capability at both in vitro and in vivo level, suggesting its clinical potential for tumor imaging. Additionally, Doxorubicin (DOX), a widely used clinical chemotherapeutic drug that kill cancer cells by intercalating DNA in cellular nucleus, was immobilized onto AuNC-cRGD-Apt forming a pro-drug, AuNC-DOX-cRGD-Apt. The enhanced tumor affinity, deep tumor penetration and improved anti-tumor activity of this pro-drug were demonstrated in different tumor cell lines, tumor spheroid and tumor-bearing mouse models. Results in this study suggest not only the prospect of non-toxic AuNC modified with two targeting ligands for tumor targeted imaging, but also confirm the promising future of dual targeting AuNC as a core for the design of prodrug in the field of cancer therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Analysis of Mass Averaged Tissue Doses in CAM, CAF, MAX, and FAX

NASA Technical Reports Server (NTRS)

Slaba, Tony C.; Qualls, Garry D.; Clowdsley, Martha S.; Blattnig, Steve R.; Simonsen, Lisa C.; Walker, Steven A.; Singleterry, Robert C.

2009-01-01

To estimate astronaut health risk due to space radiation, one must have the ability to calculate exposure-related quantities averaged over specific organs and tissue types. In this study, we first examine the anatomical properties of the Computerized Anatomical Man (CAM), Computerized Anatomical Female (CAF), Male Adult voXel (MAX), and Female Adult voXel (FAX) models by comparing the masses of various tissues to the reference values specified by the International Commission on Radiological Protection (ICRP). Major discrepancies are found between the CAM and CAF tissue masses and the ICRP reference data for almost all of the tissues. We next examine the distribution of target points used with the deterministic transport code HZETRN to compute mass averaged exposure quantities. A numerical algorithm is used to generate multiple point distributions for many of the effective dose tissues identified in CAM, CAF, MAX, and FAX. It is concluded that the previously published CAM and CAF point distributions were under-sampled and that the set of point distributions presented here should be adequate for future studies involving CAM, CAF, MAX, or FAX. It is concluded that MAX and FAX are more accurate than CAM and CAF for space radiation analyses.

Effect of Patient Set-up and Respiration motion on Defining Biological Targets for Image-Guided Targeted Radiotherapy

NASA Astrophysics Data System (ADS)

McCall, Keisha C.

Identification and monitoring of sub-tumor targets will be a critical step for optimal design and evaluation of cancer therapies in general and biologically targeted radiotherapy (dose-painting) in particular. Quantitative PET imaging may be an important tool for these applications. Currently radiotherapy planning accounts for tumor motion by applying geometric margins. These margins create a motion envelope to encompass the most probable positions of the tumor, while also maintaining the appropriate tumor control and normal tissue complication probabilities. This motion envelope is effective for uniform dose prescriptions where the therapeutic dose is conformed to the external margins of the tumor. However, much research is needed to establish the equivalent margins for non-uniform fields, where multiple biological targets are present and each target is prescribed its own dose level. Additionally, the size of the biological targets and close proximity make it impractical to apply planning margins on the sub-tumor level. Also, the extent of high dose regions must be limited to avoid excessive dose to the surrounding tissue. As such, this research project is an investigation of the uncertainty within quantitative PET images of moving and displaced dose-painting targets, and an investigation of the residual errors that remain after motion management. This included characterization of the changes in PET voxel-values as objects are moved relative to the discrete sampling interval of PET imaging systems (SPECIFIC AIM 1). Additionally, the repeatability of PET distributions and the delineating dose-painting targets were measured (SPECIFIC AIM 2). The effect of imaging uncertainty on the dose distributions designed using these images (SPECIFIC AIM 3) has also been investigated. This project also included analysis of methods to minimize motion during PET imaging and reduce the dosimetric impact of motion/position-induced imaging uncertainty (SPECIFIC AIM 4).

In vivo mapping of current density distribution in brain tissues during deep brain stimulation (DBS)

NASA Astrophysics Data System (ADS)

Sajib, Saurav Z. K.; Oh, Tong In; Kim, Hyung Joong; Kwon, Oh In; Woo, Eung Je

2017-01-01

New methods for in vivo mapping of brain responses during deep brain stimulation (DBS) are indispensable to secure clinical applications. Assessment of current density distribution, induced by internally injected currents, may provide an alternative method for understanding the therapeutic effects of electrical stimulation. The current flow and pathway are affected by internal conductivity, and can be imaged using magnetic resonance-based conductivity imaging methods. Magnetic resonance electrical impedance tomography (MREIT) is an imaging method that can enable highly resolved mapping of electromagnetic tissue properties such as current density and conductivity of living tissues. In the current study, we experimentally imaged current density distribution of in vivo canine brains by applying MREIT to electrical stimulation. The current density maps of three canine brains were calculated from the measured magnetic flux density data. The absolute current density values of brain tissues, including gray matter, white matter, and cerebrospinal fluid were compared to assess the active regions during DBS. The resulting current density in different tissue types may provide useful information about current pathways and volume activation for adjusting surgical planning and understanding the therapeutic effects of DBS.

Preparation and Immunoaffinity Depletion of Fresh Frozen Tissue Homogenates for Mass Spectrometry-Based Proteomics in the Context of Drug Target/Biomarker Discovery.

PubMed

Prieto, DaRue A; Chan, King C; Johann, Donald J; Ye, Xiaoying; Whitely, Gordon; Blonder, Josip

2017-01-01

The discovery of novel drug targets and biomarkers via mass spectrometry (MS)-based proteomic analysis of clinical specimens has proven to be challenging. The wide dynamic range of protein concentration in clinical specimens and the high background/noise originating from highly abundant proteins in tissue homogenates and serum/plasma encompass two major analytical obstacles. Immunoaffinity depletion of highly abundant blood-derived proteins from serum/plasma is a well-established approach adopted by numerous researchers; however, the utilization of this technique for immunodepletion of tissue homogenates obtained from fresh frozen clinical specimens is lacking. We first developed immunoaffinity depletion of highly abundant blood-derived proteins from tissue homogenates, using renal cell carcinoma as a model disease, and followed this study by applying it to different tissue types. Tissue homogenate immunoaffinity depletion of highly abundant proteins may be equally important as is the recognized need for depletion of serum/plasma, enabling more sensitive MS-based discovery of novel drug targets, and/or clinical biomarkers from complex clinical samples. Provided is a detailed protocol designed to guide the researcher through the preparation and immunoaffinity depletion of fresh frozen tissue homogenates for two-dimensional liquid chromatography, tandem mass spectrometry (2D-LC-MS/MS)-based molecular profiling of tissue specimens in the context of drug target and/or biomarker discovery.

STUDIES ON THE DISTRIBUTION AND PHOSPHATE TURNOVER OF THE ACID-SOLUBLE PHOSPHORUS COMPOUNDS IN VARIOUS NORMAL AND NEOPLASTIC TISSUES OF RATS. II. COMPARISON OF THE CHROMATOGRAMS OBTAINED WITH VARIOUS TISSUES INCLUDING TUMOURS (ENGLISH TEXT)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Horie, S.

Using a modified semi-micro gradient elution method of chromatography, the distribution of the acid-soluble nucleotides in various normal and neoplastic tissues of rats was compared and the variations of the distribution are described. The distribution and phosphate turnover of the acid-soluble phosphorus compounds were also studied by intraperitoneal injection of P/sup 32/ followed by the chromatographic analysis. The distribution patterns of nucleotides and radioactivity in liver, muscle, heart, lung, thymus, spleen, testicles, brain, fetal liver, and experimental hepatomas are illustrated and the differences between these tissues were pointed out. The characteristics of the experimental hepatoma tissue as compared with themore » normal liver tissue are as follows: The concentration of oxidized DPN was low; the incorporation of P/sup 32/ inorganic phosphate into glucose 6-phosphate and L- alpha -glycerophosphate was absent or, if any, very low; radioactivity of inorganic phosphate in the total acid-soluble radioactivity was extraordinarily high as compared with other tissues besides the liver tissue. (Abstr. Japan Med., 1: No. 9, 1961)« less

Dynamic distribution and tissue tropism of avian encephalomyelitis virus isolate XY/Q-1410 in experimentally infected Korean quail.

PubMed

Fan, Lili; Li, Zhijun; Huang, Jiali; Yang, Zengqi; Xiao, Sa; Wang, Xinglong; Dang, Ruyi; Zhang, Shuxia

2017-11-01

Avian encephalomyelitis (AE) is an important infectious poultry disease worldwide that is caused by avian encephalomyelitis virus (AEV). However, to date, the dynamic distribution of AEV in quails has not been well described. Quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry (IHC) assays were used to investigate the dynamic distribution and tissue tropism of AEV in experimentally infected Korean quail. AEV was detected in the cerebrum, cerebellum, proventriculus, intestine, liver, pancreas, spleen, bursa, lung and kidney as early as 3 days post-infection (dpi). The viral loads in the proventriculus, intestine, spleen and bursa were relatively higher than in other tissues. According to the qPCR results, AEV XY/Q-1410 infection lasted for at least 60 days in infected Korean quail. Immunohistochemistry-positive staining signals of AEV antigen were analysed by Image-Pro Plus software. A positive correlation between qPCR and IHC results was identified in most tissues. Our results provide an insight into the dynamic distribution of AEV in various tissues after infection. The distinct dynamic distribution of the viral genome in Korean quail in the early and late stages of infection suggests that AEV replication is affected by antibody levels and the maturity of the immune system of the host.

Rat health status affects bioavailability, target tissue levels, and bioactivity of grape seed flavanols.

PubMed

Margalef, Maria; Pons, Zara; Iglesias-Carres, Lisard; Quiñones, Mar; Bravo, Francisca Isabel; Arola-Arnal, Anna; Muguerza, Begoña

2017-02-01

Studying the flavanol metabolism is essential to identify bioactive compounds, as beneficial effects of flavanols have been attributed to their metabolic products. However, host-related factors, including pathological conditions, may affect flavanol metabolism and, thus, their bioactivity. This study aims to elucidate whether hypertension affects grape seed flavanol metabolism, influencing their bioactivity in relation to hypertension. Grape seed flavanols' effect on blood pressure (BP) was studied in spontaneously hypertensive rats (SHR) and healthy Wistar rats 6 h after grape seed extract administration (375 mg/kg). Animals were then sacrificed, and plasma bioavailability and aorta distribution of flavanol metabolites were studied by HPLC-MS/MS in both the groups. Grape seed flavanols were only able to decrease BP in SHR. Plasma total flavanol metabolites showed similar levels, being the difference noticed in specific metabolites' concentrations. Specifically, microbial metabolites showed quantitative and qualitative differences between both health states. Moreover, aorta total concentrations were found decreased in SHR. Interestingly, flavanol microbial metabolites were specifically increased SHR aortas, showing qualitative differences in small phenolic forms. This study demonstrates important differences in bioactivity and target tissue metabolite levels between healthy and diseased rats, indicating potential metabolites responsible of the anti-hypertensive effect. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Distribution of potential eye and tissue donors within an Australian teaching hospital.

PubMed

Dutch, Martin J; Denahy, Anthony F

2017-12-11

Eye and Tissue donation has the capacity to transform lives, yet the vast majority of potential in-hospital donors are not recognised. Studies which describe the relative importance of specific units or wards in determining the size of the donor pool are limited. The aim of this study was to map the distribution of potential Eye and Tissue donors within the study hospital. A 12-month retrospective analysis of all patient deaths at the study hospital was undertaken. The ability to donate corneal, heart valve, bone and skin tissue was investigated. Patients were classified as potential donors if they met specific age criteria and had an absence of contraindications based on electronic database search. There were 985 deaths during the study period. Deaths occurred under the care of 26 separate clinical units, and within 28 unique wards and treatment spaces. Four hundred and forty nine (45.6%) patients were identified as potential eye or tissue donors. The majority of potential donors occurred in ICU, Emergency and palliative care units. Of the subset of 328 deaths ≤ 70 years, the frequency of potential tissue donors was 55% (n = 181). ED and ICU had significantly higher frequencies of potential donor than other wards (86 and 77%, p < 0.01). The current study has identified the ED, ICU and PCUs are being important sites for potential Eye and Tissue Donors within our hospital. These will provide an important focus for future interventions to improve the rate of eye and tissue donation.

Systemic distribution, subcellular localization and differential expression of sphingosine-1-phosphate receptors in benign and malignant human tissues.

PubMed

Wang, Chunyi; Mao, Jinghe; Redfield, Samantha; Mo, Yinyuan; Lage, Janice M; Zhou, Xinchun

2014-10-01

Five sphingosine-1-phosphate receptors (S1PR): S1PR1, S1PR2, S1PR3, S1PR4 and S1PR5 (S1PR1-5) have been shown to be involved in the proliferation and progression of various cancers. However, none of the S1PRs have been systemically investigated. In this study, we performed immunohistochemistry (IHC) for S1PR1-S1PR5 on different tissues, in order to simultaneously determine the systemic distribution, subcellular localization and expression level of all five S1PRs. We constructed tissue microarrays (TMAs) from 384 formalin-fixed paraffin-embedded (FFPE) blocks containing 183 benign and 201 malignant tissues from 34 human organs/systems. Then we performed IHC for all five S1PRs simultaneously on these TMA slides. The distribution, subcellular localization and expression of each S1PR were determined for each tissue. The data in benign and malignant tissues from the same organ/tissue were then compared using the Student's t-test. In order to reconfirm the subcellular localization of each S1PR as determined by IHC, immunocytochemistry (ICC) was performed on several malignant cell lines. We found that all five S1PRs are widely distributed in multiple human organs/systems. All S1PRs are expressed in both the cytoplasm and nucleus, except S1PR3, whose IHC signals are only seen in the nucleus. Interestingly, the S1PRs are rarely expressed on cellular membranes. Each S1PR is unique in its organ distribution, subcellular localization and expression level in benign and malignant tissues. Among the five S1PRs, S1PR5 has the highest expression level (in either the nucleus or cytoplasm), with S1PR1, 3, 2 and 4 following in descending order. Strong nuclear expression was seen for S1PR1, S1PR3 and S1PR5, whereas S1PR2 and S1PR4 show only weak staining. Four organs/tissues (adrenal gland, liver, brain and colon) show significant differences in IHC scores for the multiple S1PRs (nuclear and/or cytoplasmic), nine (stomach, lymphoid tissues, lung, ovary, cervix, pancreas, skin, soft

Deep-Dive Targeted Quantification for Ultrasensitive Analysis of Proteins in Nondepleted Human Blood Plasma/Serum and Tissues

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nie, Song; Shi, Tujin; Fillmore, Thomas L.

Mass spectrometry-based targeted proteomics (e.g., selected reaction monitoring, SRM) is emerging as an attractive alternative to immunoassays for protein quantification. Recently we have made significant progress in SRM sensitivity for enabling quantification of low ng/mL to sub-ng/mL level proteins in nondepleted human blood plasma/serum without affinity enrichment. However, precise quantification of extremely low abundant but biologically important proteins (e.g., ≤100 pg/mL in blood plasma/serum) using targeted proteomics approaches still remains challenging. To address this need, we have developed an antibody-independent Deep-Dive SRM (DD-SRM) approach that capitalizes on multidimensional high-resolution reversed-phase liquid chromatography (LC) separation for target peptide enrichment combined withmore » precise selection of target peptide fractions of interest, significantly improving SRM sensitivity by ~5 orders of magnitude when compared to conventional LC-SRM. Application of DD-SRM to human serum and tissue has been demonstrated to enable precise quantification of endogenous proteins at ~10 pg/mL level in nondepleted serum and at <10 copies per cell level in tissue. Thus, DD-SRM holds great promise for precisely measuring extremely low abundance proteins or protein modifications, especially when high-quality antibody is not available.« less

Reconstruction of spatial distributions of sound velocity and absorption in soft biological tissues using model ultrasonic tomographic data

NASA Astrophysics Data System (ADS)

Burov, V. A.; Zotov, D. I.; Rumyantseva, O. D.

2014-07-01

A two-step algorithm is used to reconstruct the spatial distributions of the acoustic characteristics of soft biological tissues-the sound velocity and absorption coefficient. Knowing these distributions is urgent for early detection of benign and malignant neoplasms in biological tissues, primarily in the breast. At the first stage, large-scale distributions are estimated; at the second step, they are refined with a high resolution. Results of reconstruction on the base of model initial data are presented. The principal necessity of preliminary reconstruction of large-scale distributions followed by their being taken into account at the second step is illustrated. The use of CUDA technology for processing makes it possible to obtain final images of 1024 × 1024 samples in only a few minutes.

Gated Mesoporous Silica Nanocarriers for a "Two-Step" Targeted System to Colonic Tissue.

PubMed

González-Alvarez, Marta; Coll, Carmen; Gonzalez-Alvarez, Isabel; Giménez, Cristina; Aznar, Elena; Martínez-Bisbal, M Carmen; Lozoya-Agulló, Isabel; Bermejo, Marival; Martínez-Máñez, Ramón; Sancenón, Félix

2017-12-04

Colon targeted drug delivery is highly relevant not only to treat colonic local diseases but also for systemic therapies. Mesoporous silica nanoparticles (MSNs) have been demonstrated as useful systems for controlled drug release given their biocompatibility and the possibility of designing gated systems able to release cargo only upon the presence of certain stimuli. We report herein the preparation of three gated MSNs able to deliver their cargo triggered by different stimuli (redox ambient (S1), enzymatic hydrolysis (S2), and a surfactant or being in contact with cell membrane (S3)) and their performance in solution and in vitro with Caco-2 cells. Safranin O dye was used as a model drug to track cargo fate. Studies of cargo permeability in Caco-2 monolayers demonstrated that intracellular safranin O levels were significantly higher in Caco-2 monolayers when using MSNs compared to those of free dye. Internalization assays indicated that S2 nanoparticles were taken up by cells via endocytosis. S2 nanoparticles were selected for in vivo tests in rats. For in vivo assays, capsules were filled with S2 nanoparticles and coated with Eudragit FS 30 D to target colon. The enteric coated capsule containing the MSNs was able to deliver S2 nanoparticles in colon tissue (first step), and then nanoparticles were able to deliver safranin O inside the colonic cells after the enzymatic stimuli (second step). This resulted in high levels of safranin O in colonic tissue combined with low dye levels in plasma and body tissues. The results suggested that this combination of enzyme-responsive gated MSNs and enteric coated capsules may improve the absorption of drugs in colon to treat local diseases with a reduction of systemic effects.

Co-encapsulation of magnetic nanoparticles and doxorubicin into biodegradable microcarriers for deep tissue targeting by vascular MRI navigation.

PubMed

Pouponneau, Pierre; Leroux, Jean-Christophe; Soulez, Gilles; Gaboury, Louis; Martel, Sylvain

2011-05-01

Magnetic tumor targeting with external magnets is a promising method to increase the delivery of cytotoxic agents to tumor cells while reducing side effects. However, this approach suffers from intrinsic limitations, such as the inability to target areas within deep tissues, due mainly to a strong decrease of the magnetic field magnitude away from the magnets. Magnetic resonance navigation (MRN) involving the endovascular steering of therapeutic magnetic microcarriers (TMMC) represents a clinically viable alternative to reach deep tissues. MRN is achieved with an upgraded magnetic resonance imaging (MRI) scanner. In this proof-of-concept preclinical study, the preparation and steering of TMMC which were designed by taking into consideration the constraints of MRN and liver chemoembolization are reported. TMMC were biodegradable microparticles loaded with iron-cobalt nanoparticles and doxorubicin (DOX). These particles displayed high saturation magnetization (Ms = 72 emu g(-1)), MRI tracking compatibility (strong contrast on T2∗-weighted images), appropriate size for the blood vessel embolization (∼50 μm), and sustained release of DOX (over several days). The TMMC were successfully steered in vitro and in vivo in the rabbit model. In vivo targeting of the right or left liver lobes was achieved by MRN through the hepatic artery located 4 cm beneath the skin. Parameters such as flow velocity, TMMC release site in the artery, magnetic gradient and TMMC properties, affected the steering efficiency. These data illustrate the potential of MRN to improve drug targeting in deep tissues. Copyright © 2011 Elsevier Ltd. All rights reserved.

Salient target detection based on pseudo-Wigner-Ville distribution and Rényi entropy.

PubMed

Xu, Yuannan; Zhao, Yuan; Jin, Chenfei; Qu, Zengfeng; Liu, Liping; Sun, Xiudong

2010-02-15

We present what we believe to be a novel method based on pseudo-Wigner-Ville distribution (PWVD) and Rényi entropy for salient targets detection. In the foundation of studying the statistical property of Rényi entropy via PWVD, the residual entropy-based saliency map of an input image can be obtained. From the saliency map, target detection is completed by the simple and convenient threshold segmentation. Experimental results demonstrate the proposed method can detect targets effectively in complex ground scenes.

Targeting the Hippo Signaling Pathway for Tissue Regeneration and Cancer Therapy.

PubMed

Juan, Wen Chun; Hong, Wanjin

2016-08-30

The Hippo signaling pathway is a highly-conserved developmental pathway that plays an essential role in organ size control, tumor suppression, tissue regeneration and stem cell self-renewal. The YES-associated protein (YAP) and the transcriptional co-activator with PDZ-binding motif (TAZ) are two important transcriptional co-activators that are negatively regulated by the Hippo signaling pathway. By binding to transcription factors, especially the TEA domain transcription factors (TEADs), YAP and TAZ induce the expression of growth-promoting genes, which can promote organ regeneration after injury. Therefore, controlled activation of YAP and TAZ can be useful for regenerative medicine. However, aberrant activation of YAP and TAZ due to deregulation of the Hippo pathway or overexpression of YAP/TAZ and TEADs can promote cancer development. Hence, pharmacological inhibition of YAP and TAZ may be a useful approach to treat tumors with high YAP and/or TAZ activity. In this review, we present the mechanisms regulating the Hippo pathway, the role of the Hippo pathway in tissue repair and cancer, as well as a detailed analysis of the different strategies to target the Hippo signaling pathway and the genes regulated by YAP and TAZ for regenerative medicine and cancer therapy.

Optimal conditions for tissue perforation using high intensity focused ultrasound

NASA Astrophysics Data System (ADS)

Mochizuki, Takashi; Kihara, Taizo; Ogawa, Kouji; Tanabe, Ryoko; Yosizawa, Shin; Umemura, Shin-ichiro; Kakimoto, Takashi; Yamashita, Hiromasa; Chiba, Toshio

2012-10-01

To perforate tissue lying deep part in body, a large size transducer was assembled by combining four spherical-shaped transducers, and the optimal conditions for tissue perforation have studied using ventricle muscle of chicken as a target. The ex vivo experiments showed that ventricle muscle was successfully perforated both when it was exposed to High Intensity Focused Ultrasound (HIFU) directly and when it was exposed to HIFU through atrial muscle layer. Moreover, it was shown that calculated acoustic power distributions are well similar to the perforation patterns, and that the acoustic energy distributes very complexly near the focus. Lastly, perforation on the living rabbit bladder wall was demonstrated as a preliminary in vivo experiment.

Tissue distribution and acute toxicity of silver after single intravenous administration in mice: nano-specific and size-dependent effects.

PubMed

Recordati, Camilla; De Maglie, Marcella; Bianchessi, Silvia; Argentiere, Simona; Cella, Claudia; Mattiello, Silvana; Cubadda, Francesco; Aureli, Federica; D'Amato, Marilena; Raggi, Andrea; Lenardi, Cristina; Milani, Paolo; Scanziani, Eugenio

2016-02-29

Silver nanoparticles (AgNPs) are an important class of nanomaterials used as antimicrobial agents for a wide range of medical and industrial applications. However toxicity of AgNPs and impact of their physicochemical characteristics in in vivo models still need to be comprehensively characterized. The aim of this study was to investigate the effect of size and coating on tissue distribution and toxicity of AgNPs after intravenous administration in mice, and compare the results with those obtained after silver acetate administration. Male CD-1(ICR) mice were intravenously injected with AgNPs of different sizes (10 nm, 40 nm, 100 nm), citrate-or polyvinylpyrrolidone-coated, at a single dose of 10 mg/kg bw. An equivalent dose of silver ions was administered as silver acetate. Mice were euthanized 24 h after the treatment, and silver quantification by ICP-MS and histopathology were performed on spleen, liver, lungs, kidneys, brain, and blood. For all particle sizes, regardless of their coating, the highest silver concentrations were found in the spleen and liver, followed by lung, kidney, and brain. Silver concentrations were significantly higher in the spleen, lung, kidney, brain, and blood of mice treated with 10 nm AgNPs than those treated with larger particles. Relevant toxic effects (midzonal hepatocellular necrosis, gall bladder hemorrhage) were found in mice treated with 10 nm AgNPs, while in mice treated with 40 nm and 100 nm AgNPs lesions were milder or negligible, respectively. In mice treated with silver acetate, silver concentrations were significantly lower in the spleen and lung, and higher in the kidney than in mice treated with 10 nm AgNPs, and a different target organ of toxicity was identified (kidney). Administration of the smallest (10 nm) nanoparticles resulted in enhanced silver tissue distribution and overt hepatobiliary toxicity compared to larger ones (40 and 100 nm), while coating had no relevant impact. Distinct patterns of tissue

Magnetic Resonance Imaging of Adipose Tissue in Metabolic Dysfunction.

PubMed

Franz, Daniela; Syväri, Jan; Weidlich, Dominik; Baum, Thomas; Rummeny, Ernst J; Karampinos, Dimitrios C

2018-06-06

 Adipose tissue has become an increasingly important tissue target in medicine. It plays a central role in the storage and release of energy throughout the human body and has recently gained interest for its endocrinologic function. Magnetic resonance imaging (MRI) is an established method for quantitative direct evaluation of adipose tissue distribution, and is used increasingly as the modality of choice for metabolic phenotyping. The purpose of this review was the identification and presentation of the currently available literature on MRI of adipose tissue in metabolic dysfunction.  A PubMed (http://www.ncbi.nlm.nih.gov/pubmed) keyword search up to August 2017 without starting date limitation was performed and reference lists of relevant articles were searched.  MRI provides excellent tools for the evaluation of adipose tissue distribution and further characterization of the tissue. Standard as well as newly developed MRI techniques allow a risk stratification for the development of metabolic dysfunction and enable monitoring without the use of ionizing radiation or contrast material.   · Different types of adipose tissue play a crucial role in various types of metabolic dysfunction.. · Magnetic resonance imaging (MRI) is an excellent tool for noninvasive adipose tissue evaluation with respect to distribution, composition and metabolic activity.. · Both standard and newly developed MRI techniques can be used for risk stratification for the development of metabolic dysfunction and allow monitoring without the use of ionizing radiation or contrast material.. · Franz D, Syväri J, Weidlich D et al. Magnetic Resonance Imaging of Adipose Tissue in Metabolic Dysfunction. Fortschr Röntgenstr 2018; DOI: 10.1055/a-0612-8006. © Georg Thieme Verlag KG Stuttgart · New York.

Orientational tomography of optical axes directions distributions of multilayer biological tissues birefringent polycrystalline networks

NASA Astrophysics Data System (ADS)

Zabolotna, Natalia I.; Dovhaliuk, Rostyslav Y.

2013-09-01

We present a novel measurement method of optic axes orientation distribution which uses a relatively simple measurement setup. The principal difference of our method from other well-known methods lies in direct approach for measuring the orientation of optical axis of polycrystalline networks biological crystals. Our test polarimetry setup consists of HeNe laser, quarter wave plate, two linear polarizers and a CCD camera. We also propose a methodology for processing of measured optic axes orientation distribution which consists of evaluation of statistical, correlational and spectral moments. Such processing of obtained data can be used to classify particular tissue sample as "healthy" or "pathological". For our experiment we use thin layers of histological section of normal and muscular dystrophy tissue sections. It is shown that the difference between mentioned moments` values of normal and pathological samples can be quite noticeable with relative difference up to 6.26.

Current distribution in tissues with conducted electrical weapons operated in drive-stun mode.

PubMed

Panescu, Dorin; Kroll, Mark W; Brave, Michael

2016-08-01

The TASER® conducted electrical weapon (CEW) is best known for delivering electrical pulses that can temporarily incapacitate subjects by overriding normal motor control. The alternative drive-stun mode is less understood and the goal of this paper is to analyze the distribution of currents in tissues when the CEW is operated in this mode. Finite element modeling (FEM) was used to approximate current density in tissues with boundary electrical sources placed 40 mm apart. This separation was equivalent to the distance between drive-stun mode TASER X26™, X26P, X2 CEW electrodes located on the device itself and between those located on the expended CEW cartridge. The FEMs estimated the amount of current flowing through various body tissues located underneath the electrodes. The FEM simulated the attenuating effects of both a thin and of a normal layer of fat. The resulting current density distributions were used to compute the residual amount of current flowing through deeper layers of tissue. Numerical modeling estimated that the skin, fat and skeletal muscle layers passed at least 86% or 91% of total CEW current, assuming a thin or normal fat layer thickness, respectively. The current density and electric field strength only exceeded thresholds which have increased probability for ventricular fibrillation (VFTJ), or for cardiac capture (CCTE), in the skin and the subdermal fat layers. The fat layer provided significant attenuation of drive-stun CEW currents. Beyond the skeletal muscle layer, only fractional amounts of the total CEW current were estimated to flow. The regions presenting risk for VF induction or for cardiac capture were well away from the typical heart depth.

Deciphering membrane-associated molecular processes in target tissue of autoimmune uveitis by label-free quantitative mass spectrometry.

PubMed

Hauck, Stefanie M; Dietter, Johannes; Kramer, Roxane L; Hofmaier, Florian; Zipplies, Johanna K; Amann, Barbara; Feuchtinger, Annette; Deeg, Cornelia A; Ueffing, Marius

2010-10-01

Autoimmune uveitis is a blinding disease presenting with autoantibodies against eye-specific proteins as well as autoagressive T cells invading and attacking the immune-privileged target tissue retina. The molecular events enabling T cells to invade and attack the tissue have remained elusive. Changes in membrane protein expression patterns between diseased and healthy stages are especially interesting because initiating events of disease will most likely occur at membranes. Since disease progression is accompanied with a break-down of the blood-retinal barrier, serum-derived proteins mask the potential target tissue-related changes. To overcome this limitation, we used membrane-enriched fractions derived from retinas of the only available spontaneous animal model for the disease equine recurrent uveitis, and compared expression levels by a label-free LC-MSMS-based strategy to healthy control samples. We could readily identify a total of 893 equine proteins with 57% attributed to the Gene Ontology project term "membrane." Of these, 179 proteins were found differentially expressed in equine recurrent uveitis tissue. Pathway enrichment analyses indicated an increase in proteins related to antigen processing and presentation, TNF receptor signaling, integrin cell surface interactions and focal adhesions. Additionally, loss of retina-specific proteins reflecting decrease of vision was observed as well as an increase in Müller glial cell-specific proteins indicating glial reactivity. Selected protein candidates (caveolin 1, integrin alpha 1 and focal adhesion kinase) were validated by immunohistochemistry and tissue staining pattern pointed to a significant increase of these proteins at the level of the outer limiting membrane which is part of the outer blood-retinal barrier. Taken together, the membrane enrichment in combination with LC-MSMS-based label-free quantification greatly increased the sensitivity of the comparative tissue profiling and resulted in detection

Induction of Non-Targeted Stress Responses in Mammary Tissues by Heavy Ions

PubMed Central

Chai, Yunfei; Lam, Roy K. K.; Hamada, Nobuyuki; Kakinuma, Shizuko; Uchihori, Yukio; Yu, Peter K. N.; Hei, Tom K.

2015-01-01

Purpose Side effects related to radiation exposures are based primarily on the assumption that the detrimental effects of radiation occur in directly irradiated cells. However, several studies have reported over the years of radiation-induced non-targeted/ abscopal effects in vivo that challenge this paradigm. There is evidence that Cyclooxygenase-2 (COX2) plays an important role in modulating non-targeted effects, including DNA damages in vitro and mutagenesis in vivo. While most reports on radiation-induced non-targeted response utilize x-rays, there is little information available for heavy ions. Methods and Materials Adult female transgenic gpt delta mice were exposed to an equitoxic dose of either carbon or argon particles using the Heavy Ion Medical Accelerator in Chiba (HIMAC) at the National Institute of Radiological Sciences (NIRS) in Japan. The mice were stratified into 4 groups of 5 animals each: Control; animals irradiated under full shielding (Sham-irradiated); animals receiving whole body irradiation (WBIR); and animals receiving partial body irradiation (PBIR) to the lower abdomen with a 1 x 1 cm2 field. The doses used in the carbon ion group (4.5 Gy) and in argon particle group (1.5 Gy) have a relative biological effectiveness equivalent to a 5 Gy dose of x-rays. 24 hours after irradiation, breast tissues in and out of the irradiated field were harvested for analysis. Induction of COX2, 8-hydroxydeoxyguanosine (8-OHdG), phosphorylated histone H2AX (γ-H2AX), and apoptosis-related cysteine protease-3 (Caspase-3) antibodies were examined in the four categories of breast tissues using immunohistochemical techniques. Analysis was performed by measuring the intensity of more than 20 individual microscopic fields and comparing the relative fold difference. Results In the carbon ion group, the relative fold increase in COX2 expression was 1.01 in sham-irradiated group (p > 0.05), 3.07 in PBIR (p < 0.05) and 2.50 in WBIR (p < 0.05), respectively, when

Induction of Non-Targeted Stress Responses in Mammary Tissues by Heavy Ions.

PubMed

Wang, Tony J C; Wu, Cheng-Chia; Chai, Yunfei; Lam, Roy K K; Hamada, Nobuyuki; Kakinuma, Shizuko; Uchihori, Yukio; Yu, Peter K N; Hei, Tom K

2015-01-01

Side effects related to radiation exposures are based primarily on the assumption that the detrimental effects of radiation occur in directly irradiated cells. However, several studies have reported over the years of radiation-induced non-targeted/ abscopal effects in vivo that challenge this paradigm. There is evidence that Cyclooxygenase-2 (COX2) plays an important role in modulating non-targeted effects, including DNA damages in vitro and mutagenesis in vivo. While most reports on radiation-induced non-targeted response utilize x-rays, there is little information available for heavy ions. Adult female transgenic gpt delta mice were exposed to an equitoxic dose of either carbon or argon particles using the Heavy Ion Medical Accelerator in Chiba (HIMAC) at the National Institute of Radiological Sciences (NIRS) in Japan. The mice were stratified into 4 groups of 5 animals each: Control; animals irradiated under full shielding (Sham-irradiated); animals receiving whole body irradiation (WBIR); and animals receiving partial body irradiation (PBIR) to the lower abdomen with a 1 x 1 cm2 field. The doses used in the carbon ion group (4.5 Gy) and in argon particle group (1.5 Gy) have a relative biological effectiveness equivalent to a 5 Gy dose of x-rays. 24 hours after irradiation, breast tissues in and out of the irradiated field were harvested for analysis. Induction of COX2, 8-hydroxydeoxyguanosine (8-OHdG), phosphorylated histone H2AX (γ-H2AX), and apoptosis-related cysteine protease-3 (Caspase-3) antibodies were examined in the four categories of breast tissues using immunohistochemical techniques. Analysis was performed by measuring the intensity of more than 20 individual microscopic fields and comparing the relative fold difference. In the carbon ion group, the relative fold increase in COX2 expression was 1.01 in sham-irradiated group (p > 0.05), 3.07 in PBIR (p < 0.05) and 2.50 in WBIR (p < 0.05), respectively, when compared with controls. The relative fold

TU-AB-BRB-00: New Methods to Ensure Target Coverage

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

2015-06-15

The accepted clinical method to accommodate targeting uncertainties inherent in fractionated external beam radiation therapy is to utilize GTV-to-CTV and CTV-to-PTV margins during the planning process to design a PTV-conformal static dose distribution on the planning image set. Ideally, margins are selected to ensure a high (e.g. >95%) target coverage probability (CP) in spite of inherent inter- and intra-fractional positional variations, tissue motions, and initial contouring uncertainties. Robust optimization techniques, also known as probabilistic treatment planning techniques, explicitly incorporate the dosimetric consequences of targeting uncertainties by including CP evaluation into the planning optimization process along with coverage-based planning objectives. Themore » treatment planner no longer needs to use PTV and/or PRV margins; instead robust optimization utilizes probability distributions of the underlying uncertainties in conjunction with CP-evaluation for the underlying CTVs and OARs to design an optimal treated volume. This symposium will describe CP-evaluation methods as well as various robust planning techniques including use of probability-weighted dose distributions, probability-weighted objective functions, and coverage optimized planning. Methods to compute and display the effect of uncertainties on dose distributions will be presented. The use of robust planning to accommodate inter-fractional setup uncertainties, organ deformation, and contouring uncertainties will be examined as will its use to accommodate intra-fractional organ motion. Clinical examples will be used to inter-compare robust and margin-based planning, highlighting advantages of robust-plans in terms of target and normal tissue coverage. Robust-planning limitations as uncertainties approach zero and as the number of treatment fractions becomes small will be presented, as well as the factors limiting clinical implementation of robust planning. Learning Objectives: To

Testosterone differentially regulates targets of lipid and glucose metabolism in liver, muscle and adipose tissues of the testicular feminised mouse.

PubMed

Kelly, Daniel M; Akhtar, Samia; Sellers, Donna J; Muraleedharan, Vakkat; Channer, Kevin S; Jones, T Hugh

2016-11-01

Testosterone deficiency is commonly associated with obesity, metabolic syndrome, type 2 diabetes and their clinical consequences-hepatic steatosis and atherosclerosis. The testicular feminised mouse (non-functional androgen receptor and low testosterone) develops fatty liver and aortic lipid streaks on a high-fat diet, whereas androgen-replete XY littermate controls do not. Testosterone treatment ameliorates these effects, although the underlying mechanisms remain unknown. We compared the influence of testosterone on the expression of regulatory targets of glucose, cholesterol and lipid metabolism in muscle, liver, abdominal subcutaneous and visceral adipose tissue. Testicular feminised mice displayed significantly reduced GLUT4 in muscle and glycolytic enzymes in muscle, liver and abdominal subcutaneous but not visceral adipose tissue. Lipoprotein lipase required for fatty acid uptake was only reduced in subcutaneous adipose tissue; enzymes of fatty acid synthesis were increased in liver and subcutaneous tissue. Stearoyl-CoA desaturase-1 that catalyses oleic acid synthesis and is associated with insulin resistance was increased in visceral adipose tissue and cholesterol efflux components (ABCA1, apoE) were decreased in subcutaneous and liver tissue. Master regulator nuclear receptors involved in metabolism-Liver X receptor expression was suppressed in all tissues except visceral adipose tissue, whereas PPARγ was lower in abdominal subcutaneous and visceral adipose tissue and PPARα only in abdominal subcutaneous. Testosterone treatment improved the expression (androgen receptor independent) of some targets but not all. These exploratory data suggest that androgen deficiency may reduce the buffering capability for glucose uptake and utilisation in abdominal subcutaneous and muscle and fatty acids in abdominal subcutaneous. This would lead to an overspill and uptake of excess glucose and triglycerides into visceral adipose tissue, liver and arterial walls.

Tissue factor is an angiogenic-specific receptor for factor VII-targeted immunotherapy and photodynamic therapy.

PubMed

Hu, Zhiwei; Cheng, Jijun; Xu, Jie; Ruf, Wolfram; Lockwood, Charles J

2017-02-01

Identification of target molecules specific for angiogenic vascular endothelial cells (VEC), the inner layer of pathological neovasculature, is critical for discovery and development of neovascular-targeting therapy for angiogenesis-dependent human diseases, notably cancer, macular degeneration and endometriosis, in which vascular endothelial growth factor (VEGF) plays a central pathophysiological role. Using VEGF-stimulated vascular endothelial cells (VECs) isolated from microvessels, venous and arterial blood vessels as in vitro angiogenic models and unstimulated VECs as a quiescent VEC model, we examined the expression of tissue factor (TF), a membrane-bound receptor on the angiogenic VEC models compared with quiescent VEC controls. We found that TF is specifically expressed on angiogenic VECs in a time-dependent manner in microvessels, venous and arterial vessels. TF-targeted therapeutic agents, including factor VII (fVII)-IgG1 Fc and fVII-conjugated photosensitizer, can selectively bind angiogenic VECs, but not the quiescent VECs. Moreover, fVII-targeted photodynamic therapy can selectively and completely eradicate angiogenic VECs. We conclude that TF is an angiogenic-specific receptor and the target molecule for fVII-targeted therapeutics. This study supports clinical trials of TF-targeted therapeutics for the treatment of angiogenesis-dependent diseases such as cancer, macular degeneration and endometriosis.

CdSe/ZnS Quantum Dots-Labeled Mesenchymal Stem Cells for Targeted Fluorescence Imaging of Pancreas Tissues and Therapy of Type 1 Diabetic Rats.

PubMed

Liu, Haoqi; Tang, Wei; Li, Chao; Lv, Pinlei; Wang, Zheng; Liu, Yanlei; Zhang, Cunlei; Bao, Yi; Chen, Haiyan; Meng, Xiangying; Song, Yan; Xia, Xiaoling; Pan, Fei; Cui, Daxiang; Shi, Yongquan

2015-12-01

Mesenchymal stem cells (MSCs) have been used for therapy of type 1 diabetes mellitus. However, the in vivo distribution and therapeutic effects of transplanted MSCs are not clarified well. Herein, we reported that CdSe/ZnS quantum dots-labeled MSCs were prepared for targeted fluorescence imaging and therapy of pancreas tissues in rat models with type 1 diabetes. CdSe/ZnS quantum dots were synthesized, their biocompatibility was evaluated, and then, the appropriate concentration of quantum dots was selected to label MSCs. CdSe/ZnS quantum dots-labeled MSCs were injected into mouse models with type 1 diabetes via tail vessel and then were observed by using the Bruker In-Vivo F PRO system, and the blood glucose levels were monitored for 8 weeks. Results showed that prepared CdSe/ZnS quantum dots owned good biocompatibility. Significant differences existed in distribution of quantum dots-labeled MSCs between normal control rats and diabetic rats (p < 0.05). The ratios of the fluorescence intensity (RFI) analysis showed an accumulation rate of MSCs in the pancreas of rats in the diabetes group which was about 32 %, while that in the normal control group rats was about 18 %. The blood glucose levels were also monitored for 8 weeks after quantum dots-labeled MSC injection. Statistical differences existed between the blood glucose levels of the diabetic rat control group and MSC-injected diabetic rat group (p < 0.01), and the MSC-injected diabetic rat group displayed lower blood glucose levels. In conclusion, CdSe/ZnS-labeled MSCs can target in vivo pancreas tissues in diabetic rats, and significantly reduce the blood glucose levels in diabetic rats, and own potential application in therapy of diabetic patients in the near future.

CdSe/ZnS Quantum Dots-Labeled Mesenchymal Stem Cells for Targeted Fluorescence Imaging of Pancreas Tissues and Therapy of Type 1 Diabetic Rats

NASA Astrophysics Data System (ADS)

Liu, Haoqi; Tang, Wei; Li, Chao; Lv, Pinlei; Wang, Zheng; Liu, Yanlei; Zhang, Cunlei; Bao, Yi; Chen, Haiyan; Meng, Xiangying; Song, Yan; Xia, Xiaoling; Pan, Fei; Cui, Daxiang; Shi, Yongquan

2015-06-01

Mesenchymal stem cells (MSCs) have been used for therapy of type 1 diabetes mellitus. However, the in vivo distribution and therapeutic effects of transplanted MSCs are not clarified well. Herein, we reported that CdSe/ZnS quantum dots-labeled MSCs were prepared for targeted fluorescence imaging and therapy of pancreas tissues in rat models with type 1 diabetes. CdSe/ZnS quantum dots were synthesized, their biocompatibility was evaluated, and then, the appropriate concentration of quantum dots was selected to label MSCs. CdSe/ZnS quantum dots-labeled MSCs were injected into mouse models with type 1 diabetes via tail vessel and then were observed by using the Bruker In-Vivo F PRO system, and the blood glucose levels were monitored for 8 weeks. Results showed that prepared CdSe/ZnS quantum dots owned good biocompatibility. Significant differences existed in distribution of quantum dots-labeled MSCs between normal control rats and diabetic rats ( p < 0.05). The ratios of the fluorescence intensity (RFI) analysis showed an accumulation rate of MSCs in the pancreas of rats in the diabetes group, and was about 32 %, while that in the normal control group rats was about 18 %. The blood glucose levels were also monitored for 8 weeks after quantum dots-labeled MSC injection. Statistical differences existed between the blood glucose levels of the diabetic rat control group and MSC-injected diabetic rat group ( p < 0.01), and the MSC-injected diabetic rat group displayed lower blood glucose levels. In conclusion, CdSe/ZnS-labeled MSCs can target in vivo pancreas tissues in diabetic rats, and significantly reduce the blood glucose levels in diabetic rats, and own potential application in therapy of diabetic patients in the near future.

Tracking targeted bimodal nanovaccines: immune responses and routing in cells, tissue, and whole organism.

PubMed

Cruz, Luis J; Tacken, Paul J; Zeelenberg, Ingrid S; Srinivas, Mangala; Bonetto, Fernando; Weigelin, Bettina; Eich, Christina; de Vries, I Jolanda; Figdor, Carl G

2014-12-01

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs), involved in the induction of immunity and currently exploited for antitumor immunotherapies. An optimized noninvasive imaging modality capable of determining and quantifying DC-targeted nanoparticle (NP) trajectories could provide valuable information regarding therapeutic vaccine outcome. Here, targeted poly(d,l-lactide-co-glycolide) nanoparticles (PLGA NPs) recognizing DC receptors were equipped with superparamagnetic iron oxide particles (SPIO) or gold nanoparticles with fluorescently labeled antigen. The fluorescent label allowed for rapid analysis and quantification of DC-specific uptake of targeted PLGA NPs in comparison to uptake by other cells. Transmission electron microscopy (TEM) showed that a fraction of the encapsulated antigen reached the lysosomal compartment of DCs, where SPIO and gold were already partially released. However, part of the PLGA NPs localized within the cytoplasm, as confirmed by confocal microscopy. DCs targeted with NPs carrying SPIO or fluorescent antigen were detected within lymph nodes as early as 1 h after injection by magnetic resonance imaging (MRI). Despite the fact that targeting did not markedly affect PLGA NP biodistribution on organism and tissue level, it increased delivery of NPs to DCs residing in peripheral lymph nodes and resulted in enhanced T cell proliferation. In conclusion, two imaging agents within a single carrier allows tracking of targeted PLGA NPs at the subcellular, cellular, and organismal levels, thereby facilitating the rational design of in vivo targeted vaccination strategies.

Distribution of opiate alkaloids in brain tissue of experimental animals

PubMed Central

Pilija, Vladimir; Mimica-Dukic, Neda; Budakov, Branislav; Cvjeticanin, Stanko

2012-01-01

The present study examined regional distribution of opiate alkaloids from seized heroin in brain regions of experimental animals in order to select parts with the highest content of opiates. Their analysis should contribute to resolve causes of death due to heroin intake. The tests were performed at different time periods (5, 15, 45 and 120 min) after male and female Wistar rats were treated with seized heroin. Opiate alkaloids (codeine, morphine, acetylcodeine, 6-acetylmorphine and 3,6-diacetylmorphine) were quantitatively determined in brain regions known for their high concentration of µ-opiate receptors: cortex, brainstem, amygdala and basal ganglia, by using gas chromatography–mass spectrometry (GC–MS). The highest content of opiate alkaloids in the brain tissue of female animals was found 15 min and in male animals 45 min after treatment. The highest content of opiates was determined in the basal ganglia of the animals of both genders, indicating that this part of brain tissue presents a reliable sample for identifying and assessing contents of opiates after heroin intake. PMID:23554560

The local matrix distribution and the functional development of tissue engineered cartilage, a finite element study.

PubMed

Sengers, B G; Van Donkelaar, C C; Oomens, C W J; Baaijens, F P T

2004-12-01

Assessment of the functionality of tissue engineered cartilage constructs is hampered by the lack of correlation between global measurements of extra cellular matrix constituents and the global mechanical properties. Based on patterns of matrix deposition around individual cells, it has been hypothesized previously, that mechanical functionality arises when contact occurs between zones of matrix associated with individual cells. The objective of this study is to determine whether the local distribution of newly synthesized extracellular matrix components contributes to the evolution of the mechanical properties of tissue engineered cartilage constructs. A computational homogenization approach was adopted, based on the concept of a periodic representative volume element. Local transport and immobilization of newly synthesized matrix components were described. Mechanical properties were taken dependent on the local matrix concentration and subsequently the global aggregate modulus and hydraulic permeability were derived. The transport parameters were varied to assess the effect of the evolving matrix distribution during culture. The results indicate that the overall stiffness and permeability are to a large extent insensitive to differences in local matrix distribution. This emphasizes the need for caution in the visual interpretation of tissue functionality from histology and underlines the importance of complementary measurements of the matrix's intrinsic molecular organization.

Pharmacokinetics and Tissue Distribution Study of Chlorogenic Acid from Lonicerae Japonicae Flos Following Oral Administrations in Rats

PubMed Central

Zhou, Yulu; Zhou, Ting; Pei, Qi; Liu, Shikun; Yuan, Hong

2014-01-01

Chlorogenic acid (ChA) is proposed as the major bioactive compounds of Lonicerae Japonicae Flos (LJF). Forty-two Wistar rats were randomly divided into seven groups to investigate the pharmacokinetics and tissue distribution of ChA, via oral administration of LJF extract, using ibuprofen as internal standard, employing a high performance liquid chromatography in conjunction with tandem mass spectrometry. Analytes were extracted from plasma samples and tissue homogenate by liquid–liquid extraction with acetonitrile, separated on a C 18 column by linear gradient elution, and detected by electrospray ionization mass spectrometry in negative selected multiple reaction monitoring mode. Our results successfully demonstrate that the method has satisfactory selectivity, linearity, extraction recovery, matrix effect, precision, accuracy, and stability. Using noncompartment model to study pharmacokinetics, profile revealed that ChA was rapidly absorbed and eliminated. Tissue study indicated that the highest level was observed in liver, followed by kidney, lung, heart, and spleen. In conclusion, this method was suitable for the study on pharmacokinetics and tissue distribution of ChA after oral administration. PMID:25140190

HPLC determination of strychnine and brucine in rat tissues and the distribution study of processed semen strychni.

PubMed

Chen, Jun; Hou, Ting; Fang, Yun; Chen, Zhi-peng; Liu, Xiao; Cai, Hao; Lu, Tu-lin; Yan, Guo-jun; Cai, Bao-chang

2011-01-01

A simple and low-cost HPLC method with UV absorbance detection was developed and validated to simultaneously determine strychnine and brucine, the most abundant alkaloids in the processed Semen Strychni, in rat tissues (kidney, liver, spleen, lung, heart, stomach, small intestine, brain and plasma). The tissue samples were treated with a simple liquid-liquid extraction prior to HPLC. The LOQs were in the range of 0.039-0.050 µg/ml for different tissue or plasma samples. The extraction recoveries varied from 71.63 to 98.79%. The linear range was 0.05-2 µg/ml with correlation coefficient of over 0.991. The intra- and inter-day precision was less than 15%. Then the method was used to measure the tissue distribution of strychnine and brucine after intravenous administration of 1 mg/kg crude alkaloids fraction (CAF) extracted from the processed Semen Strychni. The results revealed that strychnine and brucine possessed similar tissue distribution characterization. The highest level was observed in kidney, while the lowest level was found in brain. It was indicated that kidney might be the primary excretion organ of prototype strychnine and brucine. It was also deduced that strychnine and brucine had difficulty in crossing the blood-brain barrier. Furthermore, no long-term accumulation of strychnine and brucine was found in rat tissues.

The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications.

PubMed

Upadhyaya, Laxmi; Singh, Jay; Agarwal, Vishnu; Tewari, Ravi Prakash

2014-07-28

Over the last decade carboxymethyl chitosan (CMCS) has emerged as a promising biopolymer for the development of new drug delivery systems and improved scaffolds along with other tissue engineering devices for regenerative medicine that is currently one of the most rapidly growing fields in the life sciences. CMCS is amphiprotic ether, derived from chitosan, exhibiting enhanced aqueous solubility, excellent biocompatibility, controllable biodegradability, osteogenesis ability and numerous other outstanding physicochemical and biological properties. More strikingly, it can load hydrophobic drugs and displays strong bioactivity which highlight its suitability and extensive usage for preparing different drug delivery and tissue engineering formulations respectively. This review provides a comprehensive introduction to various types of CMCS based formulations for delivery of therapeutic agents and tissue regeneration and further describes their preparation procedures and applications in different tissues/organs. Detailed information of CMCS based nano/micro systems for targeted delivery of drugs with emphasis on cancer specific and organ specific drug delivery have been described. Further, we have discussed various CMCS based tissue engineering biomaterials along with their preparation procedures and applications in different tissues/organs. The article then, gives a brief account of therapy combining drug delivery and tissue engineering. Finally, identification of major challenges and opportunities for current and ongoing application of CMCS based systems in the field are summarised. Copyright © 2014 Elsevier B.V. All rights reserved.

Altered distributions of bone tissue mineral and collagen properties in women with fragility fractures.

PubMed

Wang, Zhen Xiang; Lloyd, Ashley A; Burket, Jayme C; Gourion-Arsiquaud, Samuel; Donnelly, Eve

2016-03-01

Heterogeneity of bone tissue properties is emerging as a potential indicator of altered bone quality in pathologic tissue. The objective of this study was to compare the distributions of tissue properties in women with and without histories of fragility fractures using Fourier transform infrared (FTIR) imaging. We extended a prior study that examined the relationship of the mean FTIR properties to fracture risk by analyzing in detail the widths and the tails of the distributions of FTIR properties in biopsies from fracture and non-fracture cohorts. The mineral and matrix properties of cortical and trabecular iliac crest tissue were compared in biopsies from women with a history of fragility fracture (+Fx; n=21, age: mean 54±SD 15y) and with no history of fragility fracture (-Fx; n=12, age: 57±5y). A subset of the patients included in the -Fx group were taking estrogen-plus-progestin hormone replacement therapy (HRT) (-Fx+HRT n=8, age: 58±5y) and were analyzed separately from patients with no history of HRT (-Fx-HRT n=4, age: 56±7y). When the FTIR parameter mean values were examined by treatment group, the trabecular tissue of -Fx-HRT patients had a lower mineral:matrix ratio (M:M) and collagen maturity (XLR) than that of -Fx+HRT patients (-22% M:M, -18% XLR) and +Fx patients (-17% M:M, -18% XLR). Across multiple FTIR parameters, tissue from the -Fx-HRT group had smaller low-tail (5th percentile) values than that from the -Fx+HRT or +Fx groups. In trabecular collagen maturity and crystallinity (XST), the -Fx-HRT group had smaller low-tail values than those in the -Fx+HRT group (-16% XLR, -5% XST) and the +Fx group (-17% XLR, -7% XST). The relatively low values of trabecular mineral:matrix ratio and collagen maturity and smaller low-tail values of collagen maturity and crystallinity observed in the -Fx-HRT group are characteristic of younger tissue. Taken together, our data suggest that the presence of newly formed tissue that includes small/imperfect crystals

Distribution of Particles in the Z-axis of Tissue Sections: Relevance for Counting Methods.

PubMed

von Bartheld, Christopher S

2012-01-01

The distribution of particles in the z-axis of thick tissue sections has gained considerable attention, primarily because of implications for the accuracy of modern stereological counting methods. Three major types of artifacts can affect these sections: loss of particles from the surfaces of tissue sections (lost caps), homogeneous collapse in the z-axis, and differential deformation in the z-axis. Initially it was assumed that thick sections were not compromised by differential shrinkage or compression (differential uniform deformation). Studies in the last decade showed that such artifacts are common and that they depend on embedding media and sectioning devices. Paraffin, glycolmethacrylate and vibratome sections are affected by this artifact, but not celloidin sections or cryostat-derived cryosections. Differential distribution of particles in the z-axis is likely due to compression of the surface areas (margins) during sectioning, resulting in differential particle densities in the core and margin of tissue sections. This deformation of tissue sections can be rapidly assessed by measuring the position of particles in the z-axis. The analysis is complicated by potential secondary effects on section surfaces through loss of particles, the so-called "lost caps" phenomenon. Secondary effects necessitate the use of guard spaces, while their use in case of primary effects (compression due to sectioning) would enhance the artifact's impact on bias. Symmetric versus asymmetric patterns of z-axis distortion can give clues to distinguish primary and secondary effects. Studies that use the optical disector need to take these parameters into account to minimize biases.

Pharmacokinetic evaluation of tissue distribution of pirfenidone and its metabolites for idiopathic pulmonary fibrosis therapy.

PubMed

Togami, Kohei; Kanehira, Yukimune; Tada, Hitoshi

2015-05-01

Pirfenidone is the first and only clinically used anti-fibrotic drug for the treatment of idiopathic pulmonary fibrosis (IPF). It was reported previously that pirfenidone metabolites (5-hydroxypirfenidone and 5-carboxypirfenidone) also have anti-fibrotic effects. The present study evaluated the distribution of pirfenidone and its metabolites in the lung, liver and kidney tissues in rats. The time course for the different concentrations of pirfenidone, 5-hydroxypirfenidone and 5-carboxypirfenidone in the lung tissue following oral administration (30 mg/kg) to rats was lower than that in plasma, and the area under the drug concentration-time curve (AUC) ratios of lung/plasma for pirfenidone, 5-hydroxypirfenidone and 5-carboxypirfenidone were 0.52, 0.40 and 0.61, respectively. In in vitro transport experiments, the basolateral-to-apical transport of pirfenidone and its metabolites through the model of lung epithelial cell (Calu-3) monolayers was not significantly different from their apical-to-basolateral transport. In binding experiments, the binding rate of these drugs to the lung tissue was lower than that to the plasma protein. These findings suggest that the low distribution of pirfenidone and its metabolites in the lungs was based on their low affinities with lung tissue and not the transport characteristics of lung epithelial cells. On the other hand, the AUC ratios of liver/plasma for pirfenidone and 5-carboxypirfenidone were 2.3 and 6.5 and the AUC ratios of kidney/plasma were 1.5 and 20, respectively. The binding rates to the liver and kidney tissues were higher than those to the plasma protein. These results suggest that high concentrations of these drugs were found in the liver and kidney tissues. Copyright © 2014 John Wiley & Sons, Ltd.

Insulin resistance, hepatic lipid and adipose tissue distribution in HIV-infected men.

PubMed

He, Qing; Engelson, Ellen S; Ionescu, Gabriel; Glesby, Marshall J; Albu, Jeanine B; Kotler, Donald P

2008-01-01

A large proportion of HIV-infected patients on antiretroviral medication develop insulin resistance, especially in the context of fat redistribution. This study investigates the interrelationships among fat distribution, hepatic lipid content, and insulin resistance in HIV-infected men. We performed a cross-sectional analysis of baseline data from 23 HIV-infected participants in three prospective clinical studies. Magnetic resonance spectroscopy was used to quantify hepatic lipid concentrations. Magnetic resonance imaging was used to quantify whole-body adipose tissue compartments: that is, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes, as well as the intermuscular adipose tissue (IMAT) subcompartment and the omental-mesenteric adipose tissue (OMAT) and retroperitoneal adipose tissue (RPAT) subcompartments of VAT. The homeostasis model for assessment of insulin resistance (HOMA-IR) was calculated from fasting glucose and insulin concentrations. Hepatic lipid content correlated significantly with total VAT (r = 0.62, P = 0.0014), but not with SAT (r = 0.053, P = 0.81). In univariate analysis, hepatic lipid content was associated with the OMAT (r = 0.67, P = 0.0004) and RPAT (r = 0.53, P = 0.009) subcompartments; HOMA-IR correlated with both VAT and hepatic lipid contents (r = 0.61, P = 0.057 and r = 0.68, P = 0.0012, respectively). In stepwise linear regression models, hepatic lipid had the strongest associations with OMAT and with HOMA-IR. Hepatic lipid content is associated with VAT volume, especially the OMAT subcompartment, in HIV-infected men. Hepatic lipid content is associated with insulin resistance in HIV-infected men. Hepatic lipid content might mediate the relationship between VAT and insulin resistance among treated, HIV-infected men.

Insulin resistance, hepatic lipid and adipose tissue distribution in HIV infected men

PubMed Central

He, Qing; Engelson, Ellen S.; Ionescu, Gabriel; Glesby, Marshall J.; Albu, Jeanine B.; Kotler, Donald P.

2010-01-01

Background A large proportion of HIV-infected subjects on antiretroviral medication develop insulin resistance, especially in the context of fat redistribution. This study investigates the interrelationships among fat distribution, hepatic lipid content, and insulin resistance in HIV-infected men. Design and methods We performed a cross-sectional analysis of baseline data from twenty-three HIV-infected participants in 3 prospective clinical studies. Magnetic resonance spectroscopy was applied to quantify hepatic lipid concentrations. Magnetic resonance imaging was used to quantify whole body adipose tissue compartments, i.e., subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes as well as inter-muscular adipose tissue (IMAT) subcompartment, and omental-mesenteric adipose tissue (OMAT) and retroperitoneal adipose tissue (RPAT) subcompartments of VAT. Homeostasis model for assessment of insulin resistance (HOMA-IR) was calculated from fasting glucose and insulin concentrations. Results Hepatic lipid content correlated significantly with total VAT (r=0.62, p=0.0014) but not with SAT (r=0.053, p=0.81). In univariate analysis, hepatic lipid content was associated with the OMAT (r=0.67, p=0.0004) and RPAT (r=0.53, p=0.009) subcompartments; HOMA-IR correlated with both VAT and hepatic lipid contents (r=0.61, p=0.057 and 0.68, p=0.0012, respectively). In stepwise linear regression models, hepatic lipid had the strongest associations with OMAT and with HOMA-IR. Conclusion Hepatic lipid content is associated with VAT volume, especially the omental-mesenteric subcompartment, in HIV-infected men. Hepatic lipid content is associated with insulin resistance in HIV-infected men. Hepatic lipid content might mediate the relationship between VAT and insulin resistance among treated, HIV-infected men. PMID:18572755

Thermal infrared images to quantify thermal ablation effects of acid and base on target tissues

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Ran, E-mail: jliubme@tsinghua.edu.cn, E-mail: liuran@tsinghua.edu.cn; Liu, Jing, E-mail: jliubme@tsinghua.edu.cn, E-mail: liuran@tsinghua.edu.cn; Wang, Jia

Hyperthermia (42-46°C), treatment of tumor tissue through elevated temperature, offers several advantages including high cost-effectiveness, highly targeted ablation and fewer side effects and hence higher safety level over traditional therapies such as chemotherapy and radiotherapy. Recently, hyperthermia using heat release through exothermic acid-base neutralization comes into view owing to its relatively safe products of salt and water and highly confined ablation. However, lack of quantitative understanding of the spatial and temporal temperature profiles that are produced by simultaneous diffusion of liquid chemical and its chemical reaction within tumor tissue impedes the application of this method. This article is dedicated tomore » quantify thermal ablation effects of acid and base both individually and as in neutralization via infrared captured thermal images. A theoretical model is used to approximate specific heat absorption rate (SAR) based on experimental measurements that contrast two types of tissue, normal pork and pig liver. According to the computation, both pork and liver tissue has a higher ability in absorbing hydrochloric acid (HCl) than sodium hydroxide, hence suggesting that a reduced dosage for HCl is appropriate in a surgery. The heating effect depends heavily on the properties of tissue types and amount of chemical reagents administered. Given thermal parameters such as SAR for different tissues, a computational model can be made in predicting temperature transitions which will be helpful in planning and optimizing surgical hyperthermia procedures.« less

Thermal infrared images to quantify thermal ablation effects of acid and base on target tissues

NASA Astrophysics Data System (ADS)

Liu, Ran; Wang, Jia; Liu, Jing

2015-07-01

Hyperthermia (42-46°C), treatment of tumor tissue through elevated temperature, offers several advantages including high cost-effectiveness, highly targeted ablation and fewer side effects and hence higher safety level over traditional therapies such as chemotherapy and radiotherapy. Recently, hyperthermia using heat release through exothermic acid-base neutralization comes into view owing to its relatively safe products of salt and water and highly confined ablation. However, lack of quantitative understanding of the spatial and temporal temperature profiles that are produced by simultaneous diffusion of liquid chemical and its chemical reaction within tumor tissue impedes the application of this method. This article is dedicated to quantify thermal ablation effects of acid and base both individually and as in neutralization via infrared captured thermal images. A theoretical model is used to approximate specific heat absorption rate (SAR) based on experimental measurements that contrast two types of tissue, normal pork and pig liver. According to the computation, both pork and liver tissue has a higher ability in absorbing hydrochloric acid (HCl) than sodium hydroxide, hence suggesting that a reduced dosage for HCl is appropriate in a surgery. The heating effect depends heavily on the properties of tissue types and amount of chemical reagents administered. Given thermal parameters such as SAR for different tissues, a computational model can be made in predicting temperature transitions which will be helpful in planning and optimizing surgical hyperthermia procedures.

Target-object integration, attention distribution, and object orientation interactively modulate object-based selection.

PubMed

Al-Janabi, Shahd; Greenberg, Adam S

2016-10-01

The representational basis of attentional selection can be object-based. Various studies have suggested, however, that object-based selection is less robust than spatial selection across experimental paradigms. We sought to examine the manner by which the following factors might explain this variation: Target-Object Integration (targets 'on' vs. part 'of' an object), Attention Distribution (narrow vs. wide), and Object Orientation (horizontal vs. vertical). In Experiment 1, participants discriminated between two targets presented 'on' an object in one session, or presented as a change 'of' an object in another session. There was no spatial cue-thus, attention was initially focused widely-and the objects were horizontal or vertical. We found evidence of object-based selection only when targets constituted a change 'of' an object. Additionally, object orientation modulated the sign of object-based selection: We observed a same-object advantage for horizontal objects, but a same-object cost for vertical objects. In Experiment 2, an informative cue preceded a single target presented 'on' an object or as a change 'of' an object (thus, attention was initially focused narrowly). Unlike in Experiment 1, we found evidence of object-based selection independent of target-object integration. We again found that the sign of selection was modulated by the objects' orientation. This result may reflect a meridian effect, which emerged due to anisotropies in the cortical representations when attention is oriented endogenously. Experiment 3 revealed that object orientation did not modulate object-based selection when attention was oriented exogenously. Our findings suggest that target-object integration, attention distribution, and object orientation modulate object-based selection, but only in combination.

Biochemical Fractionation and Stable Isotope Dilution Liquid Chromatography-mass Spectrometry for Targeted and Microdomain-specific Protein Quantification in Human Postmortem Brain Tissue*

PubMed Central

MacDonald, Matthew L.; Ciccimaro, Eugene; Prakash, Amol; Banerjee, Anamika; Seeholzer, Steven H.; Blair, Ian A.; Hahn, Chang-Gyu

2012-01-01

Synaptic architecture and its adaptive changes require numerous molecular events that are both highly ordered and complex. A majority of neuropsychiatric illnesses are complex trait disorders, in which multiple etiologic factors converge at the synapse via many signaling pathways. Investigating the protein composition of synaptic microdomains from human patient brain tissues will yield valuable insights into the interactions of risk genes in many disorders. These types of studies in postmortem tissues have been limited by the lack of proper study paradigms. Thus, it is necessary not only to develop strategies to quantify protein and post-translational modifications at the synapse, but also to rigorously validate them for use in postmortem human brain tissues. In this study we describe the development of a liquid chromatography-selected reaction monitoring method, using a stable isotope-labeled neuronal proteome standard prepared from the brain tissue of a stable isotope-labeled mouse, for the multiplexed quantification of target synaptic proteins in mammalian samples. Additionally, we report the use of this method to validate a biochemical approach for the preparation of synaptic microdomain enrichments from human postmortem prefrontal cortex. Our data demonstrate that a targeted mass spectrometry approach with a true neuronal proteome standard facilitates accurate and precise quantification of over 100 synaptic proteins in mammalian samples, with the potential to quantify over 1000 proteins. Using this method, we found that protein enrichments in subcellular fractions prepared from human postmortem brain tissue were strikingly similar to those prepared from fresh mouse brain tissue. These findings demonstrate that biochemical fractionation methods paired with targeted proteomic strategies can be used in human brain tissues, with important implications for the study of neuropsychiatric disease. PMID:22942359

Distributed micro-radar system for detection and tracking of low-profile, low-altitude targets

NASA Astrophysics Data System (ADS)

Gorwara, Ashok; Molchanov, Pavlo

2016-05-01

Proposed airborne surveillance radar system can detect, locate, track, and classify low-profile, low-altitude targets: from traditional fixed and rotary wing aircraft to non-traditional targets like unmanned aircraft systems (drones) and even small projectiles. Distributed micro-radar system is the next step in the development of passive monopulse direction finder proposed by Stephen E. Lipsky in the 80s. To extend high frequency limit and provide high sensitivity over the broadband of frequencies, multiple angularly spaced directional antennas are coupled with front end circuits and separately connected to a direction finder processor by a digital interface. Integration of antennas with front end circuits allows to exclude waveguide lines which limits system bandwidth and creates frequency dependent phase errors. Digitizing of received signals proximate to antennas allows loose distribution of antennas and dramatically decrease phase errors connected with waveguides. Accuracy of direction finding in proposed micro-radar in this case will be determined by time accuracy of digital processor and sampling frequency. Multi-band, multi-functional antennas can be distributed around the perimeter of a Unmanned Aircraft System (UAS) and connected to the processor by digital interface or can be distributed between swarm/formation of mini/micro UAS and connected wirelessly. Expendable micro-radars can be distributed by perimeter of defense object and create multi-static radar network. Low-profile, lowaltitude, high speed targets, like small projectiles, create a Doppler shift in a narrow frequency band. This signal can be effectively filtrated and detected with high probability. Proposed micro-radar can work in passive, monostatic or bistatic regime.

SU-E-T-409: Evaluation of Tissue Composition Effect On Dose Distribution in Radiotherapy with 6 MV Photon Beam of a Medical Linac

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ghorbani, M; Tabatabaei, Z; Noghreiyan, A Vejdani

Purpose: The aim of this study is to evaluate soft tissue composition effect on dose distribution for various soft tissues and various depths in radiotherapy with 6 MV photon beam of a medical linac. Methods: A phantom and Siemens Primus linear accelerator were simulated using MCNPX Monte Carlo code. In a homogeneous cubic phantom, six types of soft tissue and three types of tissue-equivalent materials were defined separately. The soft tissues were muscle (skeletal), adipose tissue, blood (whole), breast tissue, soft tissue (9-component) and soft tissue (4-component). The tissue-equivalent materials included: water, A-150 tissue-equivalent plastic and perspex. Photon dose relativemore » to dose in 9-component soft tissue at various depths on the beam’s central axis was determined for the 6 MV photon beam. The relative dose was also calculated and compared for various MCNPX tallies including,F8, F6 and,F4. Results: The results of the relative photon dose in various materials relative to dose in 9-component soft tissue and using different tallies are reported in the form of tabulated data. Minor differences between dose distributions in various soft tissues and tissue-equivalent materials were observed. The results from F6 and F4 were practically the same but different with,F8 tally. Conclusion: Based on the calculations performed, the differences in dose distributions in various soft tissues and tissue-equivalent materials are minor but they could be corrected in radiotherapy calculations to upgrade the accuracy of the dosimetric calculations.« less

Thermal effects in tissues induced by interstitial irradiation of near infrared laser with a cylindrical diffuser

NASA Astrophysics Data System (ADS)

Le, Kelvin; Johsi, Chet; Figueroa, Daniel; Goddard, Jessica; Li, Xiaosong; Towner, Rheal A.; Saunders, Debra; Smith, Nataliya; Liu, Hong; Hode, Tomas; Nordquist, Robert E.; Chen, Wei R.

2011-03-01

Laser immunotherapy (LIT), using non-invasive laser irradiation, has resulted in promising outcomes in the treatment of late-stage cancer patients. However, the tissue absorption of laser light limits the clinical applications of LIT in patients with dark skin, or with deep tumors. The present study is designed to investigate the thermal effects of interstitial irradiation using an 805-nm laser with a cylindrical diffuser, in order to overcome the limitations of the non-invasive mode of treatment. Cow liver and rat tumors were irradiated using interstitial fiber. The temperature increase was monitored by thermocouples that were inserted into the tissue at different sites around the cylinder fiber. Three-dimensional temperature distribution in target tissues during and after interstitial laser irradiation was also determined by Proton Resonance Frequency. The preliminary results showed that the output power of laser and the optical parameters of the target tissue determined the light distribution in the tissue. The temperature distributions varied in the tissue according to the locations relative to the active tip of the cylindrical diffuser. The temperature increase is strongly related to the laser power and irradiation time. Our results using thermocouples and optical sensors indicated that the PRF method is reliable and accurate for temperature determination. Although the inhomogeneous biological tissues could result in temperature fluctuation, the temperature trend still can be reliable enough for the guidance of interstitial irradiation. While this study provides temperature profiles in tumor tissue during interstitial irradiation, the biological effects of the irradiation remain unclear. Future studies will be needed, particularly in combination with the application of immunostimulant for inducing tumor-specific immune responses in the treatment of metastatic tumors.

Targeting the Hippo Signaling Pathway for Tissue Regeneration and Cancer Therapy

PubMed Central

Juan, Wen Chun; Hong, Wanjin

2016-01-01

The Hippo signaling pathway is a highly-conserved developmental pathway that plays an essential role in organ size control, tumor suppression, tissue regeneration and stem cell self-renewal. The YES-associated protein (YAP) and the transcriptional co-activator with PDZ-binding motif (TAZ) are two important transcriptional co-activators that are negatively regulated by the Hippo signaling pathway. By binding to transcription factors, especially the TEA domain transcription factors (TEADs), YAP and TAZ induce the expression of growth-promoting genes, which can promote organ regeneration after injury. Therefore, controlled activation of YAP and TAZ can be useful for regenerative medicine. However, aberrant activation of YAP and TAZ due to deregulation of the Hippo pathway or overexpression of YAP/TAZ and TEADs can promote cancer development. Hence, pharmacological inhibition of YAP and TAZ may be a useful approach to treat tumors with high YAP and/or TAZ activity. In this review, we present the mechanisms regulating the Hippo pathway, the role of the Hippo pathway in tissue repair and cancer, as well as a detailed analysis of the different strategies to target the Hippo signaling pathway and the genes regulated by YAP and TAZ for regenerative medicine and cancer therapy. PMID:27589805

Tissue- and stage-specific Wnt target gene expression is controlled subsequent to β-catenin recruitment to cis-regulatory modules.

PubMed

Nakamura, Yukio; de Paiva Alves, Eduardo; Veenstra, Gert Jan C; Hoppler, Stefan

2016-06-01

Key signalling pathways, such as canonical Wnt/β-catenin signalling, operate repeatedly to regulate tissue- and stage-specific transcriptional responses during development. Although recruitment of nuclear β-catenin to target genomic loci serves as the hallmark of canonical Wnt signalling, mechanisms controlling stage- or tissue-specific transcriptional responses remain elusive. Here, a direct comparison of genome-wide occupancy of β-catenin with a stage-matched Wnt-regulated transcriptome reveals that only a subset of β-catenin-bound genomic loci are transcriptionally regulated by Wnt signalling. We demonstrate that Wnt signalling regulates β-catenin binding to Wnt target genes not only when they are transcriptionally regulated, but also in contexts in which their transcription remains unaffected. The transcriptional response to Wnt signalling depends on additional mechanisms, such as BMP or FGF signalling for the particular genes we investigated, which do not influence β-catenin recruitment. Our findings suggest a more general paradigm for Wnt-regulated transcriptional mechanisms, which is relevant for tissue-specific functions of Wnt/β-catenin signalling in embryonic development but also for stem cell-mediated homeostasis and cancer. Chromatin association of β-catenin, even to functional Wnt-response elements, can no longer be considered a proxy for identifying transcriptionally Wnt-regulated genes. Context-dependent mechanisms are crucial for transcriptional activation of Wnt/β-catenin target genes subsequent to β-catenin recruitment. Our conclusions therefore also imply that Wnt-regulated β-catenin binding in one context can mark Wnt-regulated transcriptional target genes for different contexts. © 2016. Published by The Company of Biologists Ltd.

Distribution of lymphatic tissues and autonomic nerves in supporting ligaments around the cervix uteri.

PubMed

Zhang, Jianping; Feng, Lanlan; Lu, Yi; Guo, Dongxia; Xi, Tengteng; Wang, Xiaochun

2013-05-01

To investigate the distribution of lymphatic tissues and nerves in the supporting ligaments around the cervix uteri for their tomographical relationship, 9 adult female cadavers were used in this study. Following the incision of all supporting ligaments around the cervix, hematoxylin and esosin (H&E) and immunohistochemical staining of various sections of these ligaments was performed to enable the distribution of lymph tissues and autonomic nerves to be observed. Four lymph nodes were identified in three cadaver specimens. Three lymph nodes were present at a distance of 2.0 cm from the cervix in the cranial side of the cardinal ligaments (CLs), and one lymph node was located at a distance of 4.0 cm from the cervix in the cranial side of the uterosacral ligament (USL). The lymphatic vessels were dispersed in the CLs, scattered in the cervical side of the USLs, and occasionally distributed in the vesicouterine ligaments (VULs). In the CLs, parasympathetic nerves were located at the pelvic lateral wall and went downwards and medially into the cervix, while sympathetic fibers were located in the middle and lower parts of the ligaments. In the USLs, the autonomic nerves, which consisted primarily of sympathetic fibers, went downwards and laterally from the pelvic wall to the cervix. In the VULs, parasympathetic and sympathetic nerves were located in the inner sides of the vesical veins in the deep layers of the ligaments. It is concluded that there are few lymphatic tissues in the supporting ligaments around the cervix uteri, and that nerve‑sparing radical hysterectomy (NSRH) may be a safe method for the treatment of early‑stage cervical cancer.

Tissue distribution and serum kinetics of T101 monoclonal antibody during passive anti-cancer therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shawler, D.L.; Beauregard, J.; Halpern, S.E.

We have administered fifty-six 24 hr infusions of the anti-human T-cell monoclonal antibody T101 to 10 patients with cutaneous T-cell lymphoma (CTCL) and 6 patients with chronic lymphocytic leukemia (CLL) in doses of 10, 50, 100, 150, and 500 mg. The larger doses of T101 resulted in higher, more persistent serum T101 concentrations, and CTCL patients generally developed higher serum T101 levels than CLL patients given equivalent doses. The presence of host anti-mIgG antibodies prior to infusion was associated with decreased serum concentrations of T101. Treatments that demonstrated measurable serum T101 levels were also associated with in vivo T101 bindingmore » and cytodestruction of circulating target cells. Immunofluorescence analysis of bone marrow and lymph node biopsies in CLL, and skin biopsies in CTCL, suggested that T101 had reached extravascular tumor sites. Infusion of /sup 111/In-conjugated T101 showed uptake in the liver, spleen, lymph nodes, and (in CTCL) skin infiltrates. Our data demonstrate the tissue distribution of T101 and suggest that immunoconjugates of T101 with toxins, drugs, or radioisotopes may result in better therapeutic responses.« less

Specified risk material and topographical distribution of lymphoreticular tissue of the bovine tongue.

PubMed

Rebmann, S; Kühne, M; Gasse, H; Klein, G

2010-05-01

The elimination of specified risk material from food is crucial to restricting the risk to public health arising from bovine spongiform encephalopathy. The distribution of lymphoreticular tissue as potential specified risk material of the bovine lingual tonsil is described in relation to topographical anatomical landmarks. The definition of a proper landmark is a prerequisite for establishing adequate legal regulations concerning the removal of the lingual tonsil after slaughter. The main parameter to identify the lymphoreticular tissue in this study was the immunohistochemical identification of the follicular dendritic cells in the lingual tonsil. Lymph nodules were detected in areas up to 30 mm rostral of a given macroscopic landmark, i.e., the most caudal of the papillae vallatae. This area must therefore be adequately removed from the bovine tongue in the slaughterhouse. The current method for the removal of the lingual tonsil tissue according to Regulation (EC) 999/2001 at the slaughterhouse and alternatives to this method are discussed.

A novel liquid chromatography Orbitrap mass spectrometry method with full scan for simultaneous determination of multiple bioactive constituents of Shenkang injection in rat tissues: Application to tissue distribution and pharmacokinetic studies.

PubMed

Yang, Jie; Sun, Zhi; Li, Duolu; Duan, Fei; Li, Zhuolun; Lu, Jingli; Shi, Yingying; Xu, Tanye; Zhang, Xiaojian

2018-06-07

Shenkang injection is a traditional Chinese formula with good curative effect on chronic renal failure. In this paper, a novel, rapid and sensitive ultra high performance liquid chromatography coupled with Q Exactive hybrid quadrupole orbitrap high resolution accurate mass spectrometry was developed and validated for simultaneous determination of seven bioactive constituents of Shenkang injection in rat plasma and tissues after intravenous administration. Acetonitrile was used as protein precipitation agent in biological samples dispose with carbamazepine as internal standard. The chromatographic separation was carried out on a C 18 column with a gradient mobile phase consisting of acetonitrile and water (containing 0.1% formic acid). The MS analysis was performed in the full scan positive and negative ion mode. The lower limits of quantification for the seven analytes in rat plasma and tissues were 0.1-10 ng/mL. The validated method was successfully applied to tissue distribution and pharmacokinetic studies of Shenkang injection after intravenous administration. The results of the tissue distribution study showed that the high concentration of seven constituents were primarily in the kidney tract. This is the first time to report the application of Q-Orbitrap with full scan mass spectrometry in tissue distribution and pharmacokinetic studies of Shenkang injection. This article is protected by copyright. All rights reserved.

Differentiating Immune Cell Targets in Gut-Associated Lymphoid Tissue for HIV Cure.

PubMed

Khan, Shahzada; Telwatte, Sushama; Trapecar, Martin; Yukl, Steven; Sanjabi, Shomyseh

2017-11-01

The single greatest challenge to an HIV cure is the persistence of latently infected cells containing inducible, replication-competent proviral genomes, which constitute only a small fraction of total or infected cells in the body. Although resting CD4 + T cells in the blood are a well-known source of viral rebound, more than 90% of the body's lymphocytes reside elsewhere. Many are in gut tissue, where HIV DNA levels per million CD4 + T cells are considerably higher than in the blood. Despite the significant contribution of gut tissue to viral replication and persistence, little is known about the cell types that support persistence of HIV in the gut; importantly, T cells in the gut have phenotypic, functional, and survival properties that are distinct from T cells in other tissues. The mechanisms by which latency is established and maintained will likely depend on the location and cytokine milieu surrounding the latently infected cells in each compartment. Therefore, successful HIV cure strategies require identification and characterization of the exact cell types that support viral persistence, particularly in the gut. In this review, we describe the seeding of the latent HIV reservoir in the gut mucosa; highlight the evidence for compartmentalization and depletion of T cells; summarize the immunologic consequences of HIV infection within the gut milieu; propose how the damaged gut environment may promote the latent HIV reservoir; and explore several immune cell targets in the gut and their place on the path toward HIV cure.

Determination of a novel anticancer c-Met inhibitor LS-177 in rat plasma and tissues with a validated UPLC-MS/MS method: application to pharmacokinetics and tissue distribution study.

PubMed

Ju, Ping; Liu, Zhenzhen; Jiang, Yu; Zhao, Simin; Zhang, Lunhui; Zhang, Yuanyuan; Gu, Liqiang; Tang, Xing; Bi, Kaishun; Chen, Xiaohui

2015-07-01

LS-177 is a novel small-molecule kinase inhibitor employed to interrupt the c-Met signaling pathway. A rapid and sensitive ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for determination of LS-177 in rat plasma and tissues. The biosamples were extracted by liquid-liquid extraction with methyl tert-butyl ether and separated on a C18 column (50 × 4.6 mm, 2.6 µm) using a gradient elution mobile phase consisting of acetonitrile-0.1% formic acid water. Under the optimal conditions, the selectivity of the method was satisfactory with no endogenous interference. The intraday and interday precisions (relative standard deviation) were <10.5% and the accuracy (relative error) was from -12.5 to 12.5% at all quality control levels. Excellent recovery and negligible matrix effects were observed. Stability studies showed that LS-177 was stable during the preparation and analytical processes. The UPLC-MS/MS method was successfully applied to pharmacokinetic and tissue distribution studies. The results indicated that there was no significant drug accumulation after multiple-dose oral administration of LS-177. The tissue distribution study exhibited significant higher uptakes of LS-177 in stomach, intestine, lung and liver among all of the tissues. The results in pharmacokinetics and tissue distribution may provide a meaningful basis for clinical application. Copyright © 2014 John Wiley & Sons, Ltd.

Multiscale Modeling of Antibody-Drug Conjugates: Connecting Tissue and Cellular Distribution to Whole Animal Pharmacokinetics and Potential Implications for Efficacy.

PubMed

Cilliers, Cornelius; Guo, Hans; Liao, Jianshan; Christodolu, Nikolas; Thurber, Greg M

2016-09-01

Antibody-drug conjugates exhibit complex pharmacokinetics due to their combination of macromolecular and small molecule properties. These issues range from systemic concerns, such as deconjugation of the small molecule drug during the long antibody circulation time or rapid clearance from nonspecific interactions, to local tumor tissue heterogeneity, cell bystander effects, and endosomal escape. Mathematical models can be used to study the impact of these processes on overall distribution in an efficient manner, and several types of models have been used to analyze varying aspects of antibody distribution including physiologically based pharmacokinetic (PBPK) models and tissue-level simulations. However, these processes are quantitative in nature and cannot be handled qualitatively in isolation. For example, free antibody from deconjugation of the small molecule will impact the distribution of conjugated antibodies within the tumor. To incorporate these effects into a unified framework, we have coupled the systemic and organ-level distribution of a PBPK model with the tissue-level detail of a distributed parameter tumor model. We used this mathematical model to analyze new experimental results on the distribution of the clinical antibody-drug conjugate Kadcyla in HER2-positive mouse xenografts. This model is able to capture the impact of the drug-antibody ratio (DAR) on tumor penetration, the net result of drug deconjugation, and the effect of using unconjugated antibody to drive ADC penetration deeper into the tumor tissue. This modeling approach will provide quantitative and mechanistic support to experimental studies trying to parse the impact of multiple mechanisms of action for these complex drugs.

Multiscale Modeling of Antibody Drug Conjugates: Connecting tissue and cellular distribution to whole animal pharmacokinetics and potential implications for efficacy

PubMed Central

Cilliers, Cornelius; Guo, Hans; Liao, Jianshan; Christodolu, Nikolas; Thurber, Greg M.

2016-01-01

Antibody drug conjugates exhibit complex pharmacokinetics due to their combination of macromolecular and small molecule properties. These issues range from systemic concerns, such as deconjugation of the small molecule drug during the long antibody circulation time or rapid clearance from non-specific interactions, to local tumor tissue heterogeneity, cell bystander effects, and endosomal escape. Mathematical models can be used to study the impact of these processes on overall distribution in an efficient manner, and several types of models have been used to analyze varying aspects of antibody distribution including physiologically based pharmacokinetic (PBPK) models and tissue-level simulations. However, these processes are quantitative in nature and cannot be handled qualitatively in isolation. For example, free antibody from deconjugation of the small molecule will impact the distribution of conjugated antibodies within the tumor. To incorporate these effects into a unified framework, we have coupled the systemic and organ-level distribution of a PBPK model with the tissue-level detail of a distributed parameter tumor model. We used this mathematical model to analyze new experimental results on the distribution of the clinical antibody drug conjugate Kadcyla in HER2 positive mouse xenografts. This model is able to capture the impact of the drug antibody ratio (DAR) on tumor penetration, the net result of drug deconjugation, and the effect of using unconjugated antibody to drive ADC penetration deeper into the tumor tissue. This modeling approach will provide quantitative and mechanistic support to experimental studies trying to parse the impact of multiple mechanisms of action for these complex drugs. PMID:27287046

Gold internal standard correction for elemental imaging of soft tissue sections by LA-ICP-MS: element distribution in eye microstructures.

PubMed

Konz, Ioana; Fernández, Beatriz; Fernández, M Luisa; Pereiro, Rosario; González, Héctor; Alvarez, Lydia; Coca-Prados, Miguel; Sanz-Medel, Alfredo

2013-04-01

Laser ablation coupled to inductively coupled plasma mass spectrometry has been developed for the elemental imaging of Mg, Fe and Cu distribution in histological tissue sections of fixed eyes, embedded in paraffin, from human donors (cadavers). This work presents the development of a novel internal standard correction methodology based on the deposition of a homogeneous thin gold film on the tissue surface and the use of the (197)Au(+) signal as internal standard. Sample preparation (tissue section thickness) and laser conditions were carefully optimized, and internal normalisation using (197)Au(+) was compared with (13)C(+) correction for imaging applications. (24)Mg(+), (56)Fe(+) and (63)Cu(+) distributions were investigated in histological sections of the anterior segment of the eye (including the iris, ciliary body, cornea and trabecular meshwork) and were shown to be heterogeneously distributed along those tissue structures. Reproducibility was assessed by imaging different human eye sections from the same donor and from ten different eyes from adult normal donors, which showed that similar spatial maps were obtained and therefore demonstrate the analytical potential of using (197)Au(+) as internal standard. The proposed analytical approach could offer a robust tool with great practical interest for clinical studies, e.g. to investigate trace element distribution of metals and their alterations in ocular diseases.

Targeted Ablation of the Abcc6 Gene Results in Ectopic Mineralization of Connective Tissues

PubMed Central

Klement, John F.; Matsuzaki, Yasushi; Jiang, Qiu-Jie; Terlizzi, Joseph; Choi, Hae Young; Fujimoto, Norihiro; Li, Kehua; Pulkkinen, Leena; Birk, David E.; Sundberg, John P.; Uitto, Jouni

2005-01-01

Pseudoxanthoma elasticum (PXE), characterized by connective tissue mineralization of the skin, eyes, and cardiovascular system, is caused by mutations in the ABCC6 gene. ABCC6 encodes multidrug resistance-associated protein 6 (MRP6), which is expressed primarily in the liver and kidneys. Mechanisms producing ectopic mineralization as a result of these mutations remain unclear. To elucidate this complex disease, a transgenic mouse was generated by targeted ablation of the mouse Abcc6 gene. Abcc6 null mice were negative for Mrp6 expression in the liver, and complete necropsies revealed profound mineralization of several tissues, including skin, arterial blood vessels, and retina, while heterozygous animals were indistinguishable from the wild-type mice. Particularly striking was the mineralization of vibrissae, as confirmed by von Kossa and alizarin red stains. Electron microscopy revealed mineralization affecting both elastic structures and collagen fibers. Mineralization of vibrissae was noted as early as 5 weeks of age and was progressive with age in Abcc6−/− mice but was not observed in Abcc6+/− or Abcc6+/+ mice up to 2 years of age. A total body computerized tomography scan of Abcc6−/− mice revealed mineralization in skin and subcutaneous tissue as well as in the kidneys. These data demonstrate aberrant mineralization of soft tissues in PXE-affected organs, and, consequently, these mice recapitulate features of this complex disease. PMID:16135817

An experimental and theoretical model of children’s search behavior in relation to target conspicuity and spatial distribution

NASA Astrophysics Data System (ADS)

Rosetti, Marcos Francisco; Pacheco-Cobos, Luis; Larralde, Hernán; Hudson, Robyn

2010-11-01

This work explores search trajectories of children attempting to find targets distributed on a playing field. This task, of ludic nature, was developed to test the effect of conspicuity and spatial distribution of targets on the searcher’s performance. The searcher’s path was recorded by a Global Positioning System (GPS) device attached to the child’s waist. Participants were not rewarded nor their performance rated. Variation in the conspicuity of the targets influenced search performance as expected; cryptic targets resulted in slower searches and longer, more tortuous paths. Extracting the main features of the paths showed that the children: (1) paid little attention to the spatial distribution and at least in the conspicuous condition approximately followed a nearest neighbor pattern of target collection, (2) were strongly influenced by the conspicuity of the targets. We implemented a simple statistical model for the search rules mimicking the children’s behavior at the level of individual (coarsened) steps. The model reproduced the main features of the children’s paths without the participation of memory or planning.

A new three-dimensional conformal radiotherapy (3DCRT) technique for large breast and/or high body mass index patients: evaluation of a novel fields assessment aimed to reduce extra-target-tissue irradiation.

PubMed

Gerardina, Stimato; Edy, Ippolito; Sonia, Silipigni; Cristina, Di Venanzio; Carla Germana, Rinaldi; Diego, Gaudino; Michele, Fiore; Lucio, Trodella; Maria, D'Angelillo Rolando; Sara, Ramella

2016-09-01

To develop an alternative three-dimensional treatment plan with standardized fields class solution for whole-breast radiotherapy in patients with large/pendulous breast and/or high body mass index (BMI). Two treatment plans [tangential fields and standardized five-fields technique (S5F)] for a total dose of 50 Gy/25 fractions were generated for patients with large breasts [planning target volume (PTV) >1000 cm(3) and/or BMI >25 kg m(-2)], supine positioned. S5F plans consist of two wedged tangential beams, anteroposterior: 20° for the right breast and 340° for the left breast, and posteroanterior: 181° for the right breast and 179° for the left breast. A field in field in medial-lateral beam and additional fields were added to reduce hot spot areas and extra-target-tissue irradiation and to improve dose distribution. The percentage of PTV receiving 95% of the prescribed dose (PTV V95%), percentage of PTV receiving 105% of the prescribed dose (PTV V105%), maximal dose to PTV (PTV Dmax), homogeneity index (HI) and conformity index were recorded. V10%, V20%, V105% and V107% of a "proper" normal tissue structure (body-PTV healthy tissue) were recorded. Statistical analyses were performed using SYSTAT v.12.0 (SPSS, Chicago, IL). In 38 patients included, S5F improved HI (8.4 vs 10.1; p ≤ 0.001) and significantly reduced PTV Dmax and PTV V105%. The extra-target-tissue irradiation was significantly reduced using S5F for V105% (cm(3)) and V107% (cm(3)) with a very high difference in tissue irradiation (46.6 vs 3.0 cm(3), p ≤ 0.001 for V105% and 12.2 vs 0.0 cm(3), p ≤ 0.001 for V107% for tangential field and S5F plans, respectively). Only a slight increase in low-dose extra-target-tissue irradiation (V10%) was observed (2.2719 vs 1.8261 cm(3), p = 0.002). The S5F technique in patients with large breast or high BMI increases HI and decreases hot spots in extra-target-tissues and can therefore be easily implemented in breast cancer

Evaluation of uptake and distribution of gold nanoparticles in solid tumors

NASA Astrophysics Data System (ADS)

England, Christopheri G.; Gobin, André M.; Frieboes, Hermann B.

2015-11-01

Although nanotherapeutics offer a targeted and potentially less toxic alternative to systemic chemotherapy in cancer treatment, nanotherapeutic transport is typically hindered by abnormal characteristics of tumor tissue. Once nanoparticles targeted to tumor cells arrive in the circulation of tumor vasculature, they must extravasate from irregular vessels and diffuse through the tissue to ideally reach all malignant cells in cytotoxic concentrations. The enhanced permeability and retention effect can be leveraged to promote extravasation of appropriately sized particles from tumor vasculature; however, therapeutic success remains elusive partly due to inadequate intra-tumoral transport promoting heterogeneous nanoparticle uptake and distribution. Irregular tumor vasculature not only hinders particle transport but also sustains hypoxic tissue kregions with quiescent cells, which may be unaffected by cycle-dependent chemotherapeutics released from nanoparticles and thus regrow tumor tissue following nanotherapy. Furthermore, a large proportion of systemically injected nanoparticles may become sequestered by the reticulo-endothelial system, resulting in overall diminished efficacy. We review recent work evaluating the uptake and distribution of gold nanoparticles in pre-clinical tumor models, with the goal to help improve nanotherapy outcomes. We also examine the potential role of novel layered gold nanoparticles designed to address some of these critical issues, assessing their uptake and transport in cancerous tissue.

L1-CAM in cancerous tissues.

PubMed

Gavert, Nancy; Ben-Shmuel, Amir; Raveh, Shani; Ben-Ze'ev, Avri

2008-11-01

L1-cell adhesion molecule (L1-CAM) is a cell adhesion receptor of the immunoglobulin superfamily, known for its roles in nerve cell function. While originally believed to be present only in brain cells, in recent years L1-CAM has been detected in other tissues, and in a variety of cancer cells, including some common types of human cancer. We review the prevalence of L1-CAM in human cancer, the possible mechanisms involved in L1-CAM-mediated tumorigenesis, and cancer therapies based upon L1-CAM antibody treatment. In colon cancer cells, the L1-CAM gene was identified as a target of the Wnt/beta-catenin-TCF signaling pathway, and L1-CAM was exclusively detected at the invasive front of colon and ovarian cancer tissue. The expression of L1-CAM in normal and cancer cells enhanced tumorigenesis and conferred metastasis in colon cancer cells. Antibodies against the L1-CAM ectodomain severely inhibited the proliferation of a variety of cancer cells in culture and reduced tumor burden when injected into mice harboring cancer cells expressing L1-CAM. These results, in addition to the presence of L1-CAM on the cell surface and its restricted distribution in normal tissues, make it an ideal target for tumor therapy.

Construction of ultrasonic nanobubbles carrying CAIX polypeptides to target carcinoma cells derived from various organs.

PubMed

Zhu, Lianhua; Guo, Yanli; Wang, Luofu; Fan, Xiaozhou; Xiong, Xingyu; Fang, Kejing; Xu, Dan

2017-09-29

Ultrasound molecular imaging is a novel diagnostic approach for tumors, whose key link is the construction of targeted ultrasound contrast agents. However, available targeted ultrasound contrast agents for molecular imaging of tumors are only achieving imaging in blood pool or one type tumor. No targeted ultrasound contrast agents have realized targeted ultrasound molecular imaging of tumor parenchymal cells in a variety of solid tumors so far. Carbonic anhydrase IX (CAIX) is highly expressed on cell membranes of various malignant solid tumors, so it's a good target for ultrasound molecular imaging. Here, targeted nanobubbles carrying CAIX polypeptides for targeted binding to a variety of malignant tumors were constructed, and targeted binding ability and ultrasound imaging effect in different types of tumors were evaluated. The mean diameter of lipid targeted nanobubbles was (503.7 ± 78.47) nm, and the polypeptides evenly distributed on the surfaces of targeted nanobubbles, which possessed the advantages of homogenous particle size, high stability, and good safety. Targeted nanobubbles could gather around CAIX-positive cells (786-O and Hela cells), while they cannot gather around CAIX-negative cells (BxPC-3 cells) in vitro, and the affinity of targeted nanobubbles to CAIX-positive cells were significantly higher than that to CAIX-negative cells (P < 0.05). Peak intensity and duration time of targeted nanobubbles and blank nanobubbles were different in CAIX-positive transplanted tumor tissues in vivo (P < 0.05). Moreover, targeted nanobubbles in CAIX-positive transplanted tumor tissues produced higher peak intensity and longer duration time than those in CAIX-negative transplanted tumor tissues (P < 0.05). Finally, immunofluorescence not only confirmed targeted nanobubbles could pass through blood vessels to enter in tumor tissue spaces, but also clarified imaging differences of targeted nanobubbles in different types of transplanted tumor tissues

Sensitivity of postplanning target and OAR coverage estimates to dosimetric margin distribution sampling parameters.

PubMed

Xu, Huijun; Gordon, J James; Siebers, Jeffrey V

2011-02-01

A dosimetric margin (DM) is the margin in a specified direction between a structure and a specified isodose surface, corresponding to a prescription or tolerance dose. The dosimetric margin distribution (DMD) is the distribution of DMs over all directions. Given a geometric uncertainty model, representing inter- or intrafraction setup uncertainties or internal organ motion, the DMD can be used to calculate coverage Q, which is the probability that a realized target or organ-at-risk (OAR) dose metric D, exceeds the corresponding prescription or tolerance dose. Postplanning coverage evaluation quantifies the percentage of uncertainties for which target and OAR structures meet their intended dose constraints. The goal of the present work is to evaluate coverage probabilities for 28 prostate treatment plans to determine DMD sampling parameters that ensure adequate accuracy for postplanning coverage estimates. Normally distributed interfraction setup uncertainties were applied to 28 plans for localized prostate cancer, with prescribed dose of 79.2 Gy and 10 mm clinical target volume to planning target volume (CTV-to-PTV) margins. Using angular or isotropic sampling techniques, dosimetric margins were determined for the CTV, bladder and rectum, assuming shift invariance of the dose distribution. For angular sampling, DMDs were sampled at fixed angular intervals w (e.g., w = 1 degree, 2 degrees, 5 degrees, 10 degrees, 20 degrees). Isotropic samples were uniformly distributed on the unit sphere resulting in variable angular increments, but were calculated for the same number of sampling directions as angular DMDs, and accordingly characterized by the effective angular increment omega eff. In each direction, the DM was calculated by moving the structure in radial steps of size delta (=0.1, 0.2, 0.5, 1 mm) until the specified isodose was crossed. Coverage estimation accuracy deltaQ was quantified as a function of the sampling parameters omega or omega eff and delta. The

Targeted Nanomaterials for Phototherapy

PubMed Central

Chitgupi, Upendra; Qin, Yiru; Lovell, Jonathan F.

2017-01-01

Phototherapies involve the irradiation of target tissues with light. To further enhance selectivity and potency, numerous molecularly targeted photosensitizers and photoactive nanoparticles have been developed. Active targeting typically involves harnessing the affinity between a ligand and a cell surface receptor for improved accumulation in the targeted tissue. Targeting ligands including peptides, proteins, aptamers and small molecules have been explored for phototherapy. In this review, recent examples of targeted nanomaterials used in phototherapy are summarized. PMID:29071178

Experimental determination of particle range and dose distribution in thick targets through fragmentation reactions of stable heavy ions.

PubMed

Inaniwa, Taku; Kohno, Toshiyuki; Tomitani, Takehiro; Urakabe, Eriko; Sato, Shinji; Kanazawa, Mitsutaka; Kanai, Tatsuaki

2006-09-07

In radiation therapy with highly energetic heavy ions, the conformal irradiation of a tumour can be achieved by using their advantageous features such as the good dose localization and the high relative biological effectiveness around their mean range. For effective utilization of such properties, it is necessary to evaluate the range of incident ions and the deposited dose distribution in a patient's body. Several methods have been proposed to derive such physical quantities; one of them uses positron emitters generated through projectile fragmentation reactions of incident ions with target nuclei. We have proposed the application of the maximum likelihood estimation (MLE) method to a detected annihilation gamma-ray distribution for determination of the range of incident ions in a target and we have demonstrated the effectiveness of the method with computer simulations. In this paper, a water, a polyethylene and a polymethyl methacrylate target were each irradiated with stable (12)C, (14)N, (16)O and (20)Ne beams. Except for a few combinations of incident beams and targets, the MLE method could determine the range of incident ions R(MLE) with a difference between R(MLE) and the experimental range of less than 2.0 mm under the circumstance that the measurement of annihilation gamma rays was started just after the irradiation of 61.4 s and lasted for 500 s. In the process of evaluating the range of incident ions with the MLE method, we must calculate many physical quantities such as the fluence and the energy of both primary ions and fragments as a function of depth in a target. Consequently, by using them we can obtain the dose distribution. Thus, when the mean range of incident ions is determined with the MLE method, the annihilation gamma-ray distribution and the deposited dose distribution can be derived simultaneously. The derived dose distributions in water for the mono-energetic heavy-ion beams of four species were compared with those measured with an

Target micro-displacement measurement by a "comb" structure of intensity distribution in laser plasma propulsion

NASA Astrophysics Data System (ADS)

Zheng, Z. Y.; Zhang, S. Q.; Gao, L.; Gao, H.

2015-05-01

A "comb" structure of beam intensity distribution is designed and achieved to measure a target displacement of micrometer level in laser plasma propulsion. Base on the "comb" structure, the target displacement generated by nanosecond laser ablation solid target is measured and discussed. It is found that the "comb" structure is more suitable for a thin film target with a velocity lower than tens of millimeters per second. Combing with a light-electric monitor, the `comb' structure can be used to measure a large range velocity.

Target specific delivery of anticancer drug in silk fibroin based 3D distribution model of bone-breast cancer cells.

PubMed

Subia, Bano; Dey, Tuli; Sharma, Shaily; Kundu, Subhas C

2015-02-04

To avoid the indiscriminating action of anticancer drugs, the cancer cell specific targeting of drug molecule becomes a preferred choice for the treatment. The successful screening of the drug molecules in 2D culture system requires further validation. The failure of target specific drug in animal model raises the issue of creating a platform in between the in vitro (2D) and in vivo animal testing. The metastatic breast cancer cells migrate and settle at different sites such as bone tissue. This work evaluates the in vitro 3D model of the breast cancer and bone cells to understand the cellular interactions in the presence of a targeted anticancer drug delivery system. The silk fibroin based cytocompatible 3D scaffold is used as in vitro 3D distribution model. Human breast adenocarcinoma and osteoblast like cells are cocultured to evaluate the efficiency of doxorubicin loaded folic acid conjugated silk fibroin nanoparticle as drug delivery system. Decreasing population of the cancer cells, which lower the levels of vascular endothelial growth factors, glucose consumption, and lactate production are observed in the drug treated coculture constructs. The drug treated constructs do not show any major impact on bone mineralization. The diminished expression of osteogenic markers such as osteocalcein and alkaline phosphatase are recorded. The result indicates that this type of silk based 3D in vitro coculture model may be utilized as a bridge between the traditional 2D and animal model system to evaluate the new drug molecule (s) or to reassay the known drug molecules or to develop target specific drug in cancer research.

Distribution of cyclosporine A in ocular tissues after topical administration of cyclosporine A cationic emulsions to pigmented rabbits.

PubMed

Daull, Philippe; Lallemand, Frédéric; Philips, Betty; Lambert, Grégory; Buggage, Ronald; Garrigue, Jean-Sébastien

2013-03-01

The aim of this study was to compare the ocular and systemic distribution of cyclosporine A (CsA) in rabbits after the instillation of preservative-free CsA cationic and anionic emulsions. For the single-dose pharmacokinetic (PK) study, rabbits were instilled with 50 μL of the test material. For the multiple-dose PK study, rabbits were instilled twice daily with Restasis or once daily with NOVA22007 for 10 days. At each time point, the cornea, conjunctiva, and whole blood were harvested for CsA quantification. Ocular and systemic distribution were determined after 4 times daily instillations with 50 μL of 3H-CsA cationic and anionic emulsions for 7 days. Restasis was used as a reference in all studies. Single-dose PK data demonstrated that NOVA22007 0.1% and 0.05% delivered higher CsA concentrations to the cornea than Restasis [concentration maximum (C max): 2692, 1372, and 748 ng/g, respectively] and have a better exposition (area under the curve). Conjunctival Cmax values were 1914, 696, and 849 ng/g and area under the curve values were 3984, 2796, and 2515 ng/g · h, for either dose of the cationic emulsions and Restasis, respectively. The multiple-dose PK and the 3H-CsA distribution data demonstrated that the systemic distribution after repeated instillations was low and comparable for all emulsions. These data demonstrate that the CsA cationic emulsions were more effective than Restasis at delivering CsA to target tissues, thus confirming the potential advantage of cationic emulsions over anionic emulsions as vehicle for ocular drug delivery for the treatment of ocular surface diseases.

The Metabolic Phenotype in Obesity: Fat Mass, Body Fat Distribution, and Adipose Tissue Function.

PubMed

Goossens, Gijs H

2017-01-01

The current obesity epidemic poses a major public health issue since obesity predisposes towards several chronic diseases. BMI and total adiposity are positively correlated with cardiometabolic disease risk at the population level. However, body fat distribution and an impaired adipose tissue function, rather than total fat mass, better predict insulin resistance and related complications at the individual level. Adipose tissue dysfunction is determined by an impaired adipose tissue expandability, adipocyte hypertrophy, altered lipid metabolism, and local inflammation. Recent human studies suggest that adipose tissue oxygenation may be a key factor herein. A subgroup of obese individuals - the 'metabolically healthy obese' (MHO) - have a better adipose tissue function, less ectopic fat storage, and are more insulin sensitive than obese metabolically unhealthy persons, emphasizing the central role of adipose tissue function in metabolic health. However, controversy has surrounded the idea that metabolically healthy obesity may be considered really healthy since MHO individuals are at increased (cardio)metabolic disease risk and may have a lower quality of life than normal weight subjects due to other comorbidities. Detailed metabolic phenotyping of obese persons will be invaluable in understanding the pathophysiology of metabolic disturbances, and is needed to identify high-risk individuals or subgroups, thereby paving the way for optimization of prevention and treatment strategies to combat cardiometabolic diseases. © 2017 The Author(s) Published by S. Karger GmbH, Freiburg.

Pharmacokinetics, Tissue Distribution, and Anti-Lipogenic/Adipogenic Effects of Allyl-Isothiocyanate Metabolites

PubMed Central

Ahn, Jiyun; Chung, Woo-Jae; Jang, Young Jin; Seong, Ki-Seung; Moon, Jae-Hak; Ha, Tae Youl; Jung, Chang Hwa

2015-01-01

Allyl-isothiocyanate (AITC) is an organosulfur phytochemical found in abundance in common cruciferous vegetables such as mustard, wasabi, and cabbage. Although AITC is metabolized primarily through the mercapturic acid pathway, its exact pharmacokinetics remains undefined and the biological function of AITC metabolites is still largely unknown. In this study, we evaluated the inhibitory effects of AITC metabolites on lipid accumulation in vitro and elucidated the pharmacokinetics and tissue distribution of AITC metabolites in rats. We found that AITC metabolites generally conjugate with glutathione (GSH) or N-acetylcysteine (NAC) and are distributed in most organs and tissues. Pharmacokinetic analysis showed a rapid uptake and complete metabolism of AITC following oral administration to rats. Although AITC has been reported to exhibit anti-tumor activity in bladder cancer, the potential bioactivity of its metabolites has not been explored. We found that GSH-AITC and NAC-AITC effectively inhibit adipogenic differentiation of 3T3-L1 preadipocytes and suppress expression of PPAR-γ, C/EBPα, and FAS, which are up-regulated during adipogenesis. GSH-AITC and NAC-AITC also suppressed oleic acid-induced lipid accumulation and lipogenesis in hepatocytes. Our findings suggest that AITC is almost completely metabolized in the liver and rapidly excreted in urine through the mercapturic acid pathway following administration in rats. AITC metabolites may exert anti-obesity effects through suppression of adipogenesis or lipogenesis. PMID:26317351

Pharmacokinetics, Tissue Distribution, and Anti-Lipogenic/Adipogenic Effects of Allyl-Isothiocyanate Metabolites.

PubMed

Kim, Yang-Ji; Lee, Da-Hye; Ahn, Jiyun; Chung, Woo-Jae; Jang, Young Jin; Seong, Ki-Seung; Moon, Jae-Hak; Ha, Tae Youl; Jung, Chang Hwa

2015-01-01

Allyl-isothiocyanate (AITC) is an organosulfur phytochemical found in abundance in common cruciferous vegetables such as mustard, wasabi, and cabbage. Although AITC is metabolized primarily through the mercapturic acid pathway, its exact pharmacokinetics remains undefined and the biological function of AITC metabolites is still largely unknown. In this study, we evaluated the inhibitory effects of AITC metabolites on lipid accumulation in vitro and elucidated the pharmacokinetics and tissue distribution of AITC metabolites in rats. We found that AITC metabolites generally conjugate with glutathione (GSH) or N-acetylcysteine (NAC) and are distributed in most organs and tissues. Pharmacokinetic analysis showed a rapid uptake and complete metabolism of AITC following oral administration to rats. Although AITC has been reported to exhibit anti-tumor activity in bladder cancer, the potential bioactivity of its metabolites has not been explored. We found that GSH-AITC and NAC-AITC effectively inhibit adipogenic differentiation of 3T3-L1 preadipocytes and suppress expression of PPAR-γ, C/EBPα, and FAS, which are up-regulated during adipogenesis. GSH-AITC and NAC-AITC also suppressed oleic acid-induced lipid accumulation and lipogenesis in hepatocytes. Our findings suggest that AITC is almost completely metabolized in the liver and rapidly excreted in urine through the mercapturic acid pathway following administration in rats. AITC metabolites may exert anti-obesity effects through suppression of adipogenesis or lipogenesis.

Combining Targeted Agents With Modern Radiotherapy in Soft Tissue Sarcomas

PubMed Central

Wong, Philip; Houghton, Peter; Kirsch, David G.; Finkelstein, Steven E.; Monjazeb, Arta M.; Xu-Welliver, Meng; Dicker, Adam P.; Ahmed, Mansoor; Vikram, Bhadrasain; Teicher, Beverly A.; Coleman, C. Norman; Machtay, Mitchell; Curran, Walter J.

2014-01-01

Improved understanding of soft-tissue sarcoma (STS) biology has led to better distinction and subtyping of these diseases with the hope of exploiting the molecular characteristics of each subtype to develop appropriately targeted treatment regimens. In the care of patients with extremity STS, adjunctive radiation therapy (RT) is used to facilitate limb and function, preserving surgeries while maintaining five-year local control above 85%. In contrast, for STS originating from nonextremity anatomical sites, the rate of local recurrence is much higher (five-year local control is approximately 50%) and a major cause of death and morbidity in these patients. Incorporating novel technological advancements to administer accurate RT in combination with novel radiosensitizing agents could potentially improve local control and overall survival. RT efficacy in STS can be increased by modulating biological pathways such as angiogenesis, cell cycle regulation, cell survival signaling, and cancer-host immune interactions. Previous experiences, advancements, ongoing research, and current clinical trials combining RT with agents modulating one or more of the above pathways are reviewed. The standard clinical management of patients with STS with pretreatment biopsy, neoadjuvant treatment, and primary surgery provides an opportune disease model for interrogating translational hypotheses. The purpose of this review is to outline a strategic vision for clinical translation of preclinical findings and to identify appropriate targeted agents to combine with radiotherapy in the treatment of STS from different sites and/or different histology subtypes. PMID:25326640

High-performance liquid chromatographic assay for the determination of novel triazole antifungal agents in tissue. Application to tissue distribution studies.

PubMed

Khan, J K; Montaseri, H; Poglod, M; Bu, H Z; Daneshtalab, M; Micetich, R G

2000-08-01

A simple and rugged reversed-phase high-performance liquid chromatographic method with ultraviolet absorbance detection at 263 nm was developed and validated for the analysis of novel triazole antifungal agents SYN-2869 and its derivatives in tissues. The method involved homogenization with 0.01 M phosphate buffer (pH 7.8) for lung, brain and spleen tissues. The liver and kidneys were homogenized with acetonitrile:acetone (1:1). The plasma proteins were precipitated with ice-cold acetonitrile and supernatent was evaporated to dryness. The reconstituted samples were injected onto an HPLC system. SYN-2869 was separated from the matrix components on a symmetry C(18) column using a aqueous mobile phase of acetonitrile and water with a flow rate of 1 mL/min. A step gradient of 40-80% acetonitrile eluted SYN-2869 and the internal standard (SYN-2506). The linear range was 0.5-10 microgram/g (r(2) > 0.99). The limit of quantitation was 0.5 microgram/g. The inter-day precision and accuracy for SYN 2869 standard concentration were from 2.6 to 7.4% and from -1.56 to +3.29%, respectively. The method was applied to tissue samples collected from single intravenous administration to mice to evaluate the distribution of these novel antifungal agents to different tissues. Copyright 2000 John Wiley & Sons, Ltd.

Tissue distribution and cell tropism of Brucella canis in naturally infected canine foetuses and neonates.

PubMed

de Souza, Tayse Domingues; de Carvalho, Tatiane Furtado; Mol, Juliana Pinto da Silva; Lopes, João Vítor Menezes; Silva, Monique Ferreira; da Paixão, Tatiane Alves; Santos, Renato Lima

2018-05-08

Brucella canis infection is an underdiagnosed zoonotic disease. Knowledge about perinatal brucellosis in dogs is extremely limited, although foetuses and neonates are under risk of infection due to vertical transmission. In this study, immunohistochemistry was used to determine tissue distribution and cell tropism of B. canis in canine foetuses and neonates. Diagnosis of B. canis in tissues of naturally infected pups was based on PCR and sequencing of amplicons, bacterial isolation, and immunohistochemistry, whose specificity was confirmed by laser capture microdissection. PCR positivity among 200 puppies was 21%, and nine isolates of B. canis were obtained. Tissues from 13 PCR-positive puppies (4 stillborn and 9 neonates) presented widespread immunolabeling. Stomach, intestines, kidney, nervous system, and umbilicus were positive in all animals tested. Other frequently infected organs included the liver (92%), lungs (85%), lymph nodes (69%), and spleen (62%). Immunolabeled coccobacilli occurred mostly in macrophages, but they were also observed in erythrocytes, epithelial cells of gastrointestinal mucosa, renal tubules, epidermis, adipocytes, choroid plexus, ependyma, neuroblasts, blood vessels endothelium, muscle cells, and in the intestinal lumen. These results largely expand our knowledge about perinatal brucellosis in the dog, clearly demonstrating a pantropic distribution of B. canis in naturally infected foetuses and neonates.

3D Bioprinting for Tissue and Organ Fabrication

PubMed Central

Zhang, Yu Shrike; Yang, Jingzhou; Jia, Weitao; Dell’Erba, Valeria; Assawes, Pribpandao; Shin, Su Ryon; Dokmeci, Mehmet Remzi; Oklu, Rahmi; Khademhosseini, Ali

2016-01-01

The field of regenerative medicine has progressed tremendously over the past few decades in its ability to fabricate functional tissue substitutes. Conventional approaches based on scaffolding and microengineering are limited in their capacity of producing tissue constructs with precise biomimetic properties. Three-dimensional (3D) bioprinting technology, on the other hand, promises to bridge the divergence between artificially engineered tissue constructs and native tissues. In a sense, 3D bioprinting offers unprecedented versatility to co-deliver cells and biomaterials with precise control over their compositions, spatial distributions, and architectural accuracy, therefore achieving detailed or even personalized recapitulation of the fine shape, structure, and architecture of target tissues and organs. Here we briefly describe recent progresses of 3D bioprinting technology and associated bioinks suitable for the printing process. We then focus on the applications of this technology in fabrication of biomimetic constructs of several representative tissues and organs, including blood vessel, heart, liver, and cartilage. We finally conclude with future challenges in 3D bioprinting as well as potential solutions for further development. PMID:27126775

3D Bioprinting for Tissue and Organ Fabrication.

PubMed

Zhang, Yu Shrike; Yue, Kan; Aleman, Julio; Moghaddam, Kamyar Mollazadeh; Bakht, Syeda Mahwish; Yang, Jingzhou; Jia, Weitao; Dell'Erba, Valeria; Assawes, Pribpandao; Shin, Su Ryon; Dokmeci, Mehmet Remzi; Oklu, Rahmi; Khademhosseini, Ali

2017-01-01

The field of regenerative medicine has progressed tremendously over the past few decades in its ability to fabricate functional tissue substitutes. Conventional approaches based on scaffolding and microengineering are limited in their capacity of producing tissue constructs with precise biomimetic properties. Three-dimensional (3D) bioprinting technology, on the other hand, promises to bridge the divergence between artificially engineered tissue constructs and native tissues. In a sense, 3D bioprinting offers unprecedented versatility to co-deliver cells and biomaterials with precise control over their compositions, spatial distributions, and architectural accuracy, therefore achieving detailed or even personalized recapitulation of the fine shape, structure, and architecture of target tissues and organs. Here we briefly describe recent progresses of 3D bioprinting technology and associated bioinks suitable for the printing process. We then focus on the applications of this technology in fabrication of biomimetic constructs of several representative tissues and organs, including blood vessel, heart, liver, and cartilage. We finally conclude with future challenges in 3D bioprinting as well as potential solutions for further development.

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

NASA Astrophysics Data System (ADS)

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

2014-03-01

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

Targeted in-vivo computed tomography (CT) imaging of tissue ACE using concentrated lisinopril-capped gold nanoparticle solutions

NASA Astrophysics Data System (ADS)

Daniel, Marie-Christine; Aras, Omer; Smith, Mark F.; Nan, Anjan; Fleiter, Thorsten

2010-04-01

The development of cardiac and pulmonary fibrosis have been associated with overexpression of angiotensin-converting enzyme (ACE). Moreover, ACE inhibitors, such as lisinopril, have shown a benificial effect for patients diagnosed with heart failure or systemic hypertension. Thus targeted imaging of the ACE is of crucial importance for monitoring of the tissue ACE activity as well as the treatment efficacy in heart failure. In this respect, lisinopril-capped gold nanoparticles were prepared to provide a new type of probe for targeted molecular imaging of ACE by tuned K-edge computed tomography (CT) imaging. Concentrated solutions of these modified gold nanoparticles, with a diameter around 16 nm, showed high contrast in CT imaging. These new targeted imaging agents were thus used for in vivo imaging on rat models.

Studying the distribution of deep Raman spectroscopy signals using liquid tissue phantoms with varying optical properties.

PubMed

Vardaki, Martha Z; Gardner, Benjamin; Stone, Nicholas; Matousek, Pavel

2015-08-07

In this study we employed large volume liquid tissue phantoms, consisting of a scattering agent (Intralipid), an absorption agent (Indian ink) and a synthesized calcification powder (calcium hydroxyapatite (HAP)) similar to that found in cancerous tissues (e.g. breast and prostate), to simulate human tissues. We studied experimentally the magnitude and origin of Raman signals in a transmission Raman geometry as a function of optical properties of the medium and the location of calcifications within the phantom. The goal was to inform the development of future noninvasive cancer screening applications in vivo. The results provide insight into light propagation and Raman scattering distribution in deep Raman measurements, exploring also the effect of the variation of relative absorbance of laser and Raman photons within the phantoms. Most notably when modeling breast and prostate tissues it follows that maximum signals is obtained from the front and back faces of the tissue with the central region contributing less to the measured spectrum.

Towards an orientation-distribution-based multi-scale approach for remodelling biological tissues.

PubMed

Menzel, A; Harrysson, M; Ristinmaa, M

2008-10-01

The mechanical behaviour of soft biological tissues is governed by phenomena occurring on different scales of observation. From the computational modelling point of view, a vital aspect consists of the appropriate incorporation of micromechanical effects into macroscopic constitutive equations. In this work, particular emphasis is placed on the simulation of soft fibrous tissues with the orientation of the underlying fibres being determined by distribution functions. A straightforward but convenient Taylor-type homogenisation approach links the micro- or rather meso-level of fibres to the overall macro-level and allows to reflect macroscopically orthotropic response. As a key aspect of this work, evolution equations for the fibre orientations are accounted for so that physiological effects like turnover or rather remodelling are captured. Concerning numerical applications, the derived set of equations can be embedded into a nonlinear finite element context so that first elementary simulations are finally addressed.

The direct analysis of drug distribution of rotigotine-loaded microspheres from tissue sections by LESA coupled with tandem mass spectrometry.

PubMed

Xu, Li-Xiao; Wang, Tian-Tian; Geng, Yin-Yin; Wang, Wen-Yan; Li, Yin; Duan, Xiao-Kun; Xu, Bin; Liu, Charles C; Liu, Wan-Hui

2017-09-01

The direct analysis of drug distribution of rotigotine-loaded microspheres (RoMS) from tissue sections by liquid extraction surface analysis (LESA) coupled with tandem mass spectrometry (MS/MS) was demonstrated. The RoMS distribution in rat tissues assessed by the ambient LESA-MS/MS approach without extensive or tedious sample pretreatment was compared with that obtained by a conventional liquid chromatography tandem mass spectrometry (LC-MS/MS) method in which organ excision and subsequent solvent extraction were commonly employed before analysis. Results obtained from the two were well correlated for a majority of the organs, such as muscle, liver, stomach, and hippocampus. The distribution of RoMS in the brain, however, was found to be mainly focused in the hippocampus and striatum regions as shown by the LESA-imaged profiles. The LESA approach we developed is sensitive enough, with an estimated LLOQ at 0.05 ng/mL of rotigotine in brain tissue, and information-rich with minimal sample preparation, suitable, and promising in assisting the development of new drug delivery systems for controlled drug release and protection. Graphical abstract Workflow for the LESA-MS/MS imaging of brain tissue section after intramuscular RoMS administration.

Simultaneous determination of bioactive components of Radix Angelicae Sinensis-Radix Paeoniae Alba herb couple in rat plasma and tissues by UPLC-MS/MS and its application to pharmacokinetics and tissue distribution.

PubMed

Luo, Niancui; Li, Zhenhao; Qian, Dawei; Qian, Yefei; Guo, Jianming; Duan, Jin-Ao; Zhu, Min

2014-07-15

A highly sensitive and rapid ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) has been developed and validated for simultaneous quantification of seven components in rat plasma and five components in rat tissues after oral administration of the extracts of different combination Radix Angelicae Sinensis-Radix Paeoniae Alba herb couple and has been applied to compare the different pharmacokinetics and tissue distribution properties of these bioactive components. The extracts of Radix Angelicae Sinensis (RAS), Radix Paeoniae Alba (RPA) and Radix Angelicae Sinensis-Radix Paeoniae Alba herb couple (RRHC) were orally administrated to rats, respectively. The concentrations of ferulic acid, caffeic acid, vanillic acid, ligustilide, paeoniflorin, albiflorin and oxypaeoniflorin in rat plasma and the concentrations of ferulic acid, vanillic acid, paeoniflorin, albiflorin and oxypaeoniflorin in tissues were determined by UPLC-MS/MS. The plasma samples were pretreated by protein precipitation with methanol and the tissue samples were homogenated with water and pretreated by protein precipitation with methanol. Chromatographic separation was performed on a C18 column using 0.1% formic acid-acetonitrile as mobile phase for gradient elution. A triple quadrupole (TQ) tandem mass spectrometry equipped with an electrospray ionization source was used as detector operating both in positive and negative ionization mode and operated by multiple-reaction monitoring (MRM) scanning. Noncompartmental pharmacokinetic parameters were calculated by DAS 2.0 program. The differences between each group were compared by SPSS 16.0 with Independent-Samples T-test. The pharmacokinetic parameters (such as Cmax, Tmax, T1/2, AUC0-T, MRT0-T, Vz/F or CLz/F) of all the detected components between the single herb (RAS or RPA) and herb pair (RRHP) showed significant differences (P<0.05). It indicated that the compatibility of RAS and RPA could alter the pharmacokinetics features

Sensitivity of postplanning target and OAR coverage estimates to dosimetric margin distribution sampling parameters

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu Huijun; Gordon, J. James; Siebers, Jeffrey V.

2011-02-15

Purpose: A dosimetric margin (DM) is the margin in a specified direction between a structure and a specified isodose surface, corresponding to a prescription or tolerance dose. The dosimetric margin distribution (DMD) is the distribution of DMs over all directions. Given a geometric uncertainty model, representing inter- or intrafraction setup uncertainties or internal organ motion, the DMD can be used to calculate coverage Q, which is the probability that a realized target or organ-at-risk (OAR) dose metric D{sub v} exceeds the corresponding prescription or tolerance dose. Postplanning coverage evaluation quantifies the percentage of uncertainties for which target and OAR structuresmore » meet their intended dose constraints. The goal of the present work is to evaluate coverage probabilities for 28 prostate treatment plans to determine DMD sampling parameters that ensure adequate accuracy for postplanning coverage estimates. Methods: Normally distributed interfraction setup uncertainties were applied to 28 plans for localized prostate cancer, with prescribed dose of 79.2 Gy and 10 mm clinical target volume to planning target volume (CTV-to-PTV) margins. Using angular or isotropic sampling techniques, dosimetric margins were determined for the CTV, bladder and rectum, assuming shift invariance of the dose distribution. For angular sampling, DMDs were sampled at fixed angular intervals {omega} (e.g., {omega}=1 deg., 2 deg., 5 deg., 10 deg., 20 deg.). Isotropic samples were uniformly distributed on the unit sphere resulting in variable angular increments, but were calculated for the same number of sampling directions as angular DMDs, and accordingly characterized by the effective angular increment {omega}{sub eff}. In each direction, the DM was calculated by moving the structure in radial steps of size {delta}(=0.1,0.2,0.5,1 mm) until the specified isodose was crossed. Coverage estimation accuracy {Delta}Q was quantified as a function of the sampling parameters

Tissue distribution of cells derived from the area opaca in heterospecific quail-chick blastodermal chimeras

PubMed Central

Karagenç, Levent; Sandikci, Mustafa

2010-01-01

The objective of the current study was to determine the tissue distribution of cells derived from the area opaca in heterospecific quail-chick blastodermal chimeras. Quail-chick chimeras were constructed by transferring dissociated cells from the area opaca of the stage X–XII (EG&K) quail embryo into the subgerminal cavity of the unincubated chick blastoderm. The distribution of quail cells in embryonic as well as extra-embryonic tissues of the recipient embryo were examined using the QCPN monoclonal antibody after 6 days of incubation in serial sections taken at 100-μm intervals. Data gathered in the present study demonstrated that, when introduced into the subgerminal cavity of a recipient embryo, cells of the area opaca are able to populate not only extra-embryonic structures such as the amnion and the yolk sac, but also various embryonic tissues derived from the ectoderm and less frequently the mesoderm. Ectodermal chimerism was confined mainly to the head region and was observed in tissues derived from the neural ectoderm and the surface ectoderm, including the optic cup, diencephalon and lens. Although the possibility of random incorporation of transplanted cells into these embryonic structures cannot be excluded, these results would suggest that area opaca, a peripheral ring of cells in the avian embryo destined to form the extra-embryonic ectoderm and endoderm of the yolk sac, might harbor cells that have the potential to give rise to various cell types in the recipient chick embryo, including those derived from the surface ectoderm and neural ectoderm. PMID:19900180

Visualizing spatial distribution of alectinib in murine brain using quantitative mass spectrometry imaging.

PubMed

Aikawa, Hiroaki; Hayashi, Mitsuhiro; Ryu, Shoraku; Yamashita, Makiko; Ohtsuka, Naoto; Nishidate, Masanobu; Fujiwara, Yasuhiro; Hamada, Akinobu

2016-03-30

In the development of anticancer drugs, drug concentration measurements in the target tissue have been thought to be crucial for predicting drug efficacy and safety. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is commonly used for determination of average drug concentrations; however, complete loss of spatial information in the target tissue occurs. Mass spectrometry imaging (MSI) has been recently applied as an innovative tool for detection of molecular distribution of pharmacological agents in heterogeneous targets. This study examined the intra-brain transitivity of alectinib, a novel anaplastic lymphoma kinase inhibitor, using a combination of matrix-assisted laser desorption ionization-MSI and LC-MS/MS techniques. We first analyzed the pharmacokinetic profiles in FVB mice and then examined the effect of the multidrug resistance protein-1 (MDR1) using Mdr1a/b knockout mice including quantitative distribution of alectinib in the brain. While no differences were observed between the mice for the plasma alectinib concentrations, diffuse alectinib distributions were found in the brain of the Mdr1a/b knockout versus FVB mice. These results indicate the potential for using quantitative MSI for clarifying drug distribution in the brain on a microscopic level, in addition to suggesting a possible use in designing studies for anticancer drug development and translational research.

Visualizing spatial distribution of alectinib in murine brain using quantitative mass spectrometry imaging

PubMed Central

Aikawa, Hiroaki; Hayashi, Mitsuhiro; Ryu, Shoraku; Yamashita, Makiko; Ohtsuka, Naoto; Nishidate, Masanobu; Fujiwara, Yasuhiro; Hamada, Akinobu

2016-01-01

In the development of anticancer drugs, drug concentration measurements in the target tissue have been thought to be crucial for predicting drug efficacy and safety. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is commonly used for determination of average drug concentrations; however, complete loss of spatial information in the target tissue occurs. Mass spectrometry imaging (MSI) has been recently applied as an innovative tool for detection of molecular distribution of pharmacological agents in heterogeneous targets. This study examined the intra-brain transitivity of alectinib, a novel anaplastic lymphoma kinase inhibitor, using a combination of matrix-assisted laser desorption ionization–MSI and LC-MS/MS techniques. We first analyzed the pharmacokinetic profiles in FVB mice and then examined the effect of the multidrug resistance protein-1 (MDR1) using Mdr1a/b knockout mice including quantitative distribution of alectinib in the brain. While no differences were observed between the mice for the plasma alectinib concentrations, diffuse alectinib distributions were found in the brain of the Mdr1a/b knockout versus FVB mice. These results indicate the potential for using quantitative MSI for clarifying drug distribution in the brain on a microscopic level, in addition to suggesting a possible use in designing studies for anticancer drug development and translational research. PMID:27026287

Investigation of optimal method for inducing harmonic motion in tissue using a linear ultrasound phased array--a simulation study.

PubMed

Heikkilä, Janne; Hynynen, Kullervo

2006-04-01

Many noninvasive ultrasound techniques have been developed to explore mechanical properties of soft tissues. One of these methods, Localized Harmonic Motion Imaging (LHMI), has been proposed to be used for ultrasound surgery monitoring. In LHMI, dynamic ultrasound radiation-force stimulation induces displacements in a target that can be measured using pulse-echo imaging and used to estimate the elastic properties of the target. In this initial, simulation study, the use of a one-dimensional phased array is explored for the induction of the tissue motion. The study compares three different dual-frequency and amplitude-modulated single-frequency methods for the inducing tissue motion. Simulations were computed in a homogeneous soft-tissue volume. The Rayleigh integral was used in the simulations of the ultrasound fields and the tissue displacements were computed using a finite-element method (FEM). The simulations showed that amplitude-modulated sonication using a single frequency produced the largest vibration amplitude of the target tissue. These simulations demonstrate that the properties of the tissue motion are highly dependent on the sonication method and that it is important to consider the full three-dimensional distribution of the ultrasound field for controlling the induction of tissue motion.

Multiplicity distributions of shower particles and target fragments in 84 Kr 36-emulsion interactions at 1 GeV per nucleon

NASA Astrophysics Data System (ADS)

Singh, M. K.; Soma, A. K.; Pathak, Ramji; Singh, V.

2014-03-01

This article focuses on multiplicity distributions of shower particles and target fragments for interaction of 84 Kr 36 with NIKFI BR-2 nuclear emulsion target at kinetic energy of 1 GeV per nucleon. Experimental multiplicity distributions of shower particles, grey particles, black particles and heavily ionization particles are well described by multi-component Erlang distribution of multi-source thermal model. We have observed a linear correlation in multiplicities for the above mentioned particles or fragments. Further experimental studies have shown a saturation phenomenon in shower particle multiplicity with the increase of target fragment multiplicity.

An Approach for the Visualization of Temperature Distribution in Tissues According to Changes in Ultrasonic Backscattered Energy

PubMed Central

Li, Qiang; Liu, Hao-Li; Chen, Wen-Shiang

2013-01-01

Previous studies developed ultrasound temperature-imaging methods based on changes in backscattered energy (CBE) to monitor variations in temperature during hyperthermia. In conventional CBE imaging, tracking and compensation of the echo shift due to temperature increase need to be done. Moreover, the CBE image does not enable visualization of the temperature distribution in tissues during nonuniform heating, which limits its clinical application in guidance of tissue ablation treatment. In this study, we investigated a CBE imaging method based on the sliding window technique and the polynomial approximation of the integrated CBE (ICBEpa image) to overcome the difficulties of conventional CBE imaging. We conducted experiments with tissue samples of pork tenderloin ablated by microwave irradiation to validate the feasibility of the proposed method. During ablation, the raw backscattered signals were acquired using an ultrasound scanner for B-mode and ICBEpa imaging. The experimental results showed that the proposed ICBEpa image can visualize the temperature distribution in a tissue with a very good contrast. Moreover, tracking and compensation of the echo shift were not necessary when using the ICBEpa image to visualize the temperature profile. The experimental findings suggested that the ICBEpa image, a new CBE imaging method, has a great potential in CBE-based imaging of hyperthermia and other thermal therapies. PMID:24260041

Bioconjugation of recombinant tissue plasminogen activator to magnetic nanocarriers for targeted thrombolysis

PubMed Central

Yang, Hung-Wei; Hua, Mu-Yi; Lin, Kun-Ju; Wey, Shiaw-Pyng; Tsai, Rung-Ywan; Wu, Siao-Yun; Lu, Yi-Ching; Liu, Hao-Li; Wu, Tony; Ma, Yunn-Hwa

2012-01-01

Low-toxicity magnetic nanocarriers (MNCs) composed of a shell of poly [aniline-co-N-(1-one-butyric acid) aniline] over a Fe3O4 magnetic nanoparticle core were developed to carry recombinant tissue plasminogen activator (rtPA) in MNC-rtPA for targeted thrombolysis. With an average diameter of 14.8 nm, the MNCs exerted superparamagnetic properties. Up to 276 μg of active rtPA was immobilized per mg of MNCs, and the stability of the immobilized rtPA was greatly improved during storage at 4°C and 25°C. In vitro thrombolysis testing with a tubing system demonstrated that magnet-guided MNC-rtPA showed significantly improved thrombolysis compared with free rtPA and reduced the clot lysis time from 39.2 ± 3.2 minutes to 10.8 ± 4.2 minutes. In addition, magnet-guided MNC-rtPA at 20% of the regular rtPA dose restored blood flow within 15–25 minutes of treatment in a rat embolism model without triggering hematological toxicity. In conclusion, this improved system is based on magnetic targeting accelerated thrombolysis and is potentially amenable to therapeutic applications in thromboembolic diseases. PMID:23055728

VISUALIZATION OF TISSUE DISTRIBUTION AND METABOLISM OF BENZO[A]PYRENE IN EARLY EMBRYONIC MEDAKA (ORYZIAS LATIPES)

EPA Science Inventory

Fish early life stages are highly sensitive to exposure to persistent bioaccumulative toxicants (PBTs). The factors that contribute to this are unknown, but may include the distribution of PBTs to sensitive tissues during critical stages of development. Multiphoton laser scannin...

[Distributions of H3K27me3 and its modification enzymes in different tissues of mice].

PubMed

Wang, Yuying; Wang, Xinli; Zhang, Ran; Zhang, Zhiyan; Wang, Yu; Yang, Bo; Wang, Guanjie; Zhang, Xin; Ma, Fuhao; Xu, Hongye; Wu, Xiaohui; Zhang, Feng; Li, Qing

2017-11-01

Objective To investigate the levels of trimethylated histone 3 at lysine residue 27 (H3K27me3) and its modification enzymes Zeste gene enhancer homolog 2 (EZH2), lysine-specific demethylase 6B (Kdm6B/JMJD3) and lysine-specific demethylase 6A (Kdm6A/UTX) in tissues and organs of 7-day and 2-month postnatal mice. Methods Immunohistochemistry was used to detect the expressions of H3K27me3 and its modification enzymes EZH2, JMJD3 and UTX in the brain, salivary glands, back fat, thymus, lung, heart, stomach, intestines, liver, testes, and skin of 7-day and 2-month mice. Real-time quantitative PCR was used to confirm the results. The relationships between H3K27me3 and its modification enzymes were analyzed statistically. Results Immunohistochemistry showed H3K27me3 persistently present in all examined tissues of 7-day and 2-month mice. EZH2 was persistently expressed in the brain, heart, liver, and skin of 7-day and 2-month mice, but only expressed in the salivary glands, adipose tissues, thymus, lung, intestines, and testes of 2-month mice. JMJD3 was expressed in the brain, salivary glands, adipose tissues, lung, heart, stomach, intestines, testes, skin of 7-day mice, but was not expressed in the lung, adipose tissues and stomach of 2-month mice. UTX was expressed in the brain, salivary glands, adipose tissues, lung, heart, testes, skin of 7-day mice, but only expressed in the testes of 2-month mice. Most mRNA of H3K27 modification enzymes were moderately or highly expressed as their immunohistochemical results were positive. Conclusion There was H3K27me3 persistently present in the all examined tissues at different stages. EZH2 was mostly expressed in the brain, salivary glands, adipose tissues, thymus, lung, heart, intestines, liver, testes and skin of 2-month-old mice. JMJD3 and UTX were mostly expressed in the brain, salivary glands, adipose tissues, lung, heart, skin and testes of 7-day-old mice. No significant association was found between the distribution of H3K

Predicting volume of distribution with decision tree-based regression methods using predicted tissue:plasma partition coefficients.

PubMed

Freitas, Alex A; Limbu, Kriti; Ghafourian, Taravat

2015-01-01

Volume of distribution is an important pharmacokinetic property that indicates the extent of a drug's distribution in the body tissues. This paper addresses the problem of how to estimate the apparent volume of distribution at steady state (Vss) of chemical compounds in the human body using decision tree-based regression methods from the area of data mining (or machine learning). Hence, the pros and cons of several different types of decision tree-based regression methods have been discussed. The regression methods predict Vss using, as predictive features, both the compounds' molecular descriptors and the compounds' tissue:plasma partition coefficients (Kt:p) - often used in physiologically-based pharmacokinetics. Therefore, this work has assessed whether the data mining-based prediction of Vss can be made more accurate by using as input not only the compounds' molecular descriptors but also (a subset of) their predicted Kt:p values. Comparison of the models that used only molecular descriptors, in particular, the Bagging decision tree (mean fold error of 2.33), with those employing predicted Kt:p values in addition to the molecular descriptors, such as the Bagging decision tree using adipose Kt:p (mean fold error of 2.29), indicated that the use of predicted Kt:p values as descriptors may be beneficial for accurate prediction of Vss using decision trees if prior feature selection is applied. Decision tree based models presented in this work have an accuracy that is reasonable and similar to the accuracy of reported Vss inter-species extrapolations in the literature. The estimation of Vss for new compounds in drug discovery will benefit from methods that are able to integrate large and varied sources of data and flexible non-linear data mining methods such as decision trees, which can produce interpretable models. Graphical AbstractDecision trees for the prediction of tissue partition coefficient and volume of distribution of drugs.

Target Tracking Using SePDAF under Ambiguous Angles for Distributed Array Radar.

PubMed

Long, Teng; Zhang, Honggang; Zeng, Tao; Chen, Xinliang; Liu, Quanhua; Zheng, Le

2016-09-09

Distributed array radar can improve radar detection capability and measurement accuracy. However, it will suffer cyclic ambiguity in its angle estimates according to the spatial Nyquist sampling theorem since the large sparse array is undersampling. Consequently, the state estimation accuracy and track validity probability degrades when the ambiguous angles are directly used for target tracking. This paper proposes a second probability data association filter (SePDAF)-based tracking method for distributed array radar. Firstly, the target motion model and radar measurement model is built. Secondly, the fusion result of each radar's estimation is employed to the extended Kalman filter (EKF) to finish the first filtering. Thirdly, taking this result as prior knowledge, and associating with the array-processed ambiguous angles, the SePDAF is applied to accomplish the second filtering, and then achieving a high accuracy and stable trajectory with relatively low computational complexity. Moreover, the azimuth filtering accuracy will be promoted dramatically and the position filtering accuracy will also improve. Finally, simulations illustrate the effectiveness of the proposed method.

Target Tracking Using SePDAF under Ambiguous Angles for Distributed Array Radar

PubMed Central

Long, Teng; Zhang, Honggang; Zeng, Tao; Chen, Xinliang; Liu, Quanhua; Zheng, Le

2016-01-01

Distributed array radar can improve radar detection capability and measurement accuracy. However, it will suffer cyclic ambiguity in its angle estimates according to the spatial Nyquist sampling theorem since the large sparse array is undersampling. Consequently, the state estimation accuracy and track validity probability degrades when the ambiguous angles are directly used for target tracking. This paper proposes a second probability data association filter (SePDAF)-based tracking method for distributed array radar. Firstly, the target motion model and radar measurement model is built. Secondly, the fusion result of each radar’s estimation is employed to the extended Kalman filter (EKF) to finish the first filtering. Thirdly, taking this result as prior knowledge, and associating with the array-processed ambiguous angles, the SePDAF is applied to accomplish the second filtering, and then achieving a high accuracy and stable trajectory with relatively low computational complexity. Moreover, the azimuth filtering accuracy will be promoted dramatically and the position filtering accuracy will also improve. Finally, simulations illustrate the effectiveness of the proposed method. PMID:27618058

Simultaneous confocal fluorescence microscopy and optical coherence tomography for drug distribution and tissue integrity assessment

NASA Astrophysics Data System (ADS)

Rinehart, Matthew T.; LaCroix, Jeffrey; Henderson, Marcus; Katz, David; Wax, Adam

2011-03-01

The effectiveness of microbicidal gels, topical products developed to prevent infection by sexually transmitted diseases including HIV/AIDS, is governed by extent of gel coverage, pharmacokinetics of active pharmaceutical ingredients (APIs), and integrity of vaginal epithelium. While biopsies provide localized information about drug delivery and tissue structure, in vivo measurements are preferable in providing objective data on API and gel coating distribution as well as tissue integrity. We are developing a system combining confocal fluorescence microscopy with optical coherence tomography (OCT) to simultaneously measure local concentrations and diffusion coefficients of APIs during transport from microbicidal gels into tissue, while assessing tissue integrity. The confocal module acquires 2-D images of fluorescent APIs multiple times per second allowing analysis of lateral diffusion kinetics. The custom Fourier domain OCT module has a maximum a-scan rate of 54 kHz and provides depth-resolved tissue integrity information coregistered with the confocal fluorescence measurements. The combined system is validated by imaging phantoms with a surrogate fluorophore. Time-resolved API concentration measured at fixed depths is analyzed for diffusion kinetics. This multimodal system will eventually be implemented in vivo for objective evaluation of microbicide product performance.

A new three-dimensional conformal radiotherapy (3DCRT) technique for large breast and/or high body mass index patients: evaluation of a novel fields assessment aimed to reduce extra–target-tissue irradiation

PubMed Central

Stimato, Gerardina; Ippolito, Edy; Silipigni, Sonia; Venanzio, Cristina Di; Gaudino, Diego; Fiore, Michele; Trodella, Lucio; D'Angelillo, Rolando Maria; Ramella, Sara

2016-01-01

Objective: To develop an alternative three-dimensional treatment plan with standardized fields class solution for whole-breast radiotherapy in patients with large/pendulous breast and/or high body mass index (BMI). Methods: Two treatment plans [tangential fields and standardized five-fields technique (S5F)] for a total dose of 50 Gy/25 fractions were generated for patients with large breasts [planning target volume (PTV) >1000 cm3 and/or BMI >25 kg m−2], supine positioned. S5F plans consist of two wedged tangential beams, anteroposterior: 20° for the right breast and 340° for the left breast, and posteroanterior: 181° for the right breast and 179° for the left breast. A field in field in medial–lateral beam and additional fields were added to reduce hot spot areas and extra–target-tissue irradiation and to improve dose distribution. The percentage of PTV receiving 95% of the prescribed dose (PTV V95%), percentage of PTV receiving 105% of the prescribed dose (PTV V105%), maximal dose to PTV (PTV Dmax), homogeneity index (HI) and conformity index were recorded. V10%, V20%, V105% and V107% of a “proper” normal tissue structure (body-PTV healthy tissue) were recorded. Statistical analyses were performed using SYSTAT v.12.0 (SPSS, Chicago, IL). Results: In 38 patients included, S5F improved HI (8.4 vs 10.1; p ≤ 0.001) and significantly reduced PTV Dmax and PTV V105%. The extra–target-tissue irradiation was significantly reduced using S5F for V105% (cm3) and V107% (cm3) with a very high difference in tissue irradiation (46.6 vs 3.0 cm3, p ≤ 0.001 for V105% and 12.2 vs 0.0 cm3, p ≤ 0.001 for V107% for tangential field and S5F plans, respectively). Only a slight increase in low-dose extra–target-tissue irradiation (V10%) was observed (2.2719 vs 1.8261 cm3, p = 0.002). Conclusion: The S5F technique in patients with large breast or high BMI increases HI and decreases hot spots in extra-target-tissues and can therefore be

Distribution of phthalocyanines and Raman reporters in human cancerous and noncancerous breast tissue as studied by Raman imaging.

PubMed

Brozek-Pluska, Beata; Jarota, Arkadiusz; Jablonska-Gajewicz, Joanna; Kordek, Radzislaw; Czajkowski, Wojciech; Abramczyk, Halina

2012-08-01

There is a considerable interest in the developing new diagnostic techniques allowing noninvasive tracking of the progress of therapies used to treat a cancer. Raman imaging of distribution of phthalocyanine photosensitizers may open new possibilities of Photodynamic Therapy (PDT) to treat a wide range of neoplastic lesions with improved effectiveness of treatment through precise identification of malignant areas. We have employed Raman imaging and Raman spectroscopy to analyze human breast cancer tissue that interacts with photosensitizers used in the photodynamic therapy of cancer. PCA (Principal Component Analysis) has been employed to analyze various areas of the noncancerous and cancerous breast tissues. The results show that the emission spectra combined with the Raman images are very sensitive indicators to specify the aggregation state and the distribution of phthalocyanines in the cancerous and noncancerous breast tissues. Our results provide experimental evidence on the role of aggregation of phthalocyanines as a factor of particular significance in differentiation of the normal and tumourous (cancerous or benign pathology) breast tissues. We conclude that the Raman imaging reported here has a potential to be a novel and effective photodynamic therapeutic method with improved selectivity for the treatment of breast cancer.

Projectile n distributions following charge transfer of Ar+ and Na+ in a Na Rydberg target

NASA Astrophysics Data System (ADS)

MacAdam, K. B.; Gray, L. G.; Rolfes, R. G.

1990-11-01

The n distributions produced by charge transfer of Ar+ and Na+ ions in a target of Na(nl) Rydberg atoms were extensively measured at intermediate velocities. The 60-2100-eV ions bombarded a laser-excited atomic-beam target. The projectiles were neutralized by capture into Rydberg states of Ar and Na and were analyzed by field ionization in an inhomogeneous-field detector whose response over states and energies was carefully mapped. The choice of initially prepared Na states, 24d, 25s, 28d, 29s, 33d, and 34s, allowed a comparison of l=0 and >=2 targets at nearly equal binding energies over a range of reduced velocity v~=0.187 to 1.95. Capture populates m sublevels broadly, not merely m~=0. Overlapping contributions from adiabatic and diabatic modes of field ionization were accommodated in the analysis, which used a maximum-entropy-principle parametric form to fit the observed final-state distributions. The peak of the distributions, nmax, shifts upward from a value less than the initial state ni to a value one to three units higher than ni at v~ between 0.7 and 0.9 and ultimately shifts downward below ni as v~ is further increased. The distributions become significantly sharper where the maximum upward shift occurs. Two ratios were defined to express the widths of final-state distributions in relative terms, one measuring the spread of orbital kinetic energy and the other the spread of Bohr-orbit velocity. By these ratios a universal behavior over energies, states, and projectile species is observed, and small differences between l=0 and >=2 targets may be seen. A theoretical understanding of the present results, which span velocities where both molecular and perturbative theories are normally used, will require a quantal formulation that models the free-ranging response that is a hallmark of the high-quantum-number limit.

Epithelial-mesenchymal transition: An emerging target in tissue fibrosis

PubMed Central

Li, Meirong; Luan, Fuxin; Zhao, Yali; Hao, Haojie; Zhou, Yong; Han, Weidong

2016-01-01

Epithelial-mesenchymal transition (EMT) is involved in a variety of tissue fibroses. Fibroblasts/myofibroblasts derived from epithelial cells contribute to the excessive accumulation of fibrous connective tissue in damaged tissue, which can lead to permanent scarring or organ malfunction. Therefore, EMT-related fibrosis cannot be neglected. This review highlights the findings that demonstrate the EMT to be a direct contributor to the fibroblast/myofibroblast population in the development of tissue fibrosis and helps to elucidate EMT-related anti-fibrotic strategies, which may enable the development of therapeutic interventions to suppress EMT and potentially reverse organ fibrosis. PMID:26361988

Relationship between 578-nm (copper vapor) laser beam geometry and heat distribution within biological tissues

NASA Astrophysics Data System (ADS)

Ilyasov, Ildar K.; Prikhodko, Constantin V.; Nevorotin, Alexey J.

1995-01-01

Monte Carlo (MC) simulation model and the thermoindicative tissue phantom were applied for evaluation of a depth of tissue necrosis (DTN) as a result of quasi-cw copper vapor laser (578 nm) irradiation. It has been shown that incident light focusing angle is essential for DTN. In particular, there was a significant rise in DTN parallel to elevation of this angle up to +20 degree(s)C and +5 degree(s)C for both the MC simulation and tissue phantom models, respectively, with no further increase in the necrosis depth above these angles. It is to be noted that the relationship between focusing angles and DTN values was apparently stronger for the real target compared to the MC-derived hypothetical one. To what extent these date are applicable for medical practice can be evaluated in animal models which would simulate laser-assisted therapy for PWS or related dermatologic lesions with converged 578 nm laser beams.

Bioavailability and nervous tissue distribution of pyrethroid insecticide cyfluthrin in rats.

PubMed

Rodríguez, José-Luis; Ares, Irma; Martínez, Marta; Martínez-Larrañaga, María-Rosa; Anadón, Arturo; Martínez, María-Aránzazu

2018-05-08

Toxicokinetics of cyfluthrin after single oral [20 mg/kg body weight (bw)] and intravenous (IV) (3 mg/kg bw) doses were studied in rats. Serial blood samples were obtained after oral and IV administration. Brain tissue samples were also collected after oral administration. Cyfluthrin concentrations in plasma and brain tissues (hypothalamus, striatum, hippocampus and frontal cortex) were quantified using liquid chromatography tandem mass spectrometry (LC/MS). Cyfluthrin disposition was best described by the use of a two-compartment open model. When given orally, plasma kinetics showed an extensive oral absorption of cyfluthrin and a slow elimination. The area under the concentration-time curve [AUC (0-24h) ] and maximal plasma concentration (Cmax) were 6.11 ± 1.06 mg h/L and 0.385 ± 0.051 μg/mL, respectively; β phase elimination half-life (T 1/2 β) was (17.15 ± 1.67 h). Oral bioavailability was found to be 71.60 ± 12.36%. After oral administration, cyfluthrin was widely distributed to brain tissues. AUC (0-24h) was significant higher in all tested brain tissues than in plasma. The largest discrepancy was found for hypothalamus. AUC (0-24h) , Cmax and T 1/2 β in hypothalamus were 19.36 ± 2.56 mg h/L, 1.21 ± 0.11 μg/g and 22.73 ± 1.60 h, respectively. Assuming the identified toxicokinetics parameters, this study serves to better understand mammalian toxicity of pyrethroid cyfluthrin and to design further studies to characterize its neurotoxicity. Copyright © 2018 Elsevier Ltd. All rights reserved.

Taming the Flames: Targeting White Adipose Tissue Browning in Hypermetabolic Conditions.

PubMed

Abdullahi, Abdikarim; Jeschke, Marc G

2017-12-01

In this era of increased obesity and diabetes prevalence, the browning of white adipose tissue (WAT) has emerged as a promising therapeutic target to induce weight loss and improve insulin sensitivity in this population. The browning process entails a shift in the WAT from primarily storing excess energy to the dissipation of energy as heat. However, this idealistic view of WAT browning being the savior of the metabolic syndrome has been criticized by studies in burn and cancer patients that have shown browning to be detrimental rather than beneficial. In fact, in the context of hypermetabolic states, the browning of WAT has presented with substantial clinical adverse outcomes related to cachexia, hepatic steatosis, and muscle catabolism. Therefore, the previous thought construct of understanding browning as an all-beneficial physiologic event has now been met with skepticism. In this review, we focus on current knowledge of browning of WAT and its adverse metabolic alterations during hypermetabolic states. We also discuss the regulators and signaling pathways involved in the browning process and their potential for being targeted by new or existing drugs to inhibit or alleviate browning, potentially leading to decreased hypermetabolism and improved clinical outcomes. Lastly, the imminent clinical applications of pharmacological agents are explored in the perspective of attenuating WAT browning and its associated adverse side effects reported in burn patients. Copyright © 2017 Endocrine Society.

Silymarin in liposomes and ethosomes: pharmacokinetics and tissue distribution in free-moving rats by high-performance liquid chromatography-tandem mass spectrometry.

PubMed

Chang, Li-Wen; Hou, Mei-Ling; Tsai, Tung-Hu

2014-12-03

The aim of this study was to prepare silymarin formulations (silymarin entrapped in liposomes and ethosomes, formulations referred to as LSM and ESM, respectively) to improve oral bioavailability of silymarin and evaluate its tissue distribution by liquid chromatography with tandem mass spectrometry (LC-MS/MS) in free-moving rats. Silibinin is the major active constituent of silymarin, which is the main component to be analyzed. A rapid, sensitive, and repeatable LC-MS/MS method was developed and validated in terms of precision, accuracy, and extraction recovery. Furthermore, the established method was applied to study the pharmacokinetics and tissue distribution of silymarin in rats. The size, ζ potential, and drug release of the formulations were characterized. These results showed that the LSM and ESM encapsulated formulations of silymarin may provide more efficient tissue distribution and increased oral bioavailability, thus improving its therapeutic bioactive properties in the body.

A tissue factor-cascade-targeted strategy to tumor vasculature: a combination of EGFP-EGF1 conjugation nanoparticles with photodynamic therapy.

PubMed

Shi, Wei; Yin, Yanxue; Wang, Yao; Zhang, Bo; Tan, Pei; Jiang, Ting; Mei, Heng; Deng, Jun; Wang, Huafang; Guo, Tao; Pang, Zhiqing; Hu, Yu

2017-05-09

Tumor requires tumor vasculature to supply oxygen and nutrients so as to support its continued growth, as well as provide a main route for metastatic spread. In this study, a TF-cascade-targeted strategy aiming to disrupt tumor blood vessels was developed by combination of TF-targeted HMME-loaded drug delivery system and PDT. PDT is a promising new modality in the treatment of cancers, which employs the interaction between a tumor-localizing photosensitizer and light of an appropriate wavelength to bring about ROS-induced cell death. In vitro results showed that protein EGFP-EGF1modification could significantly contribute to the uptake of nanoparticles by TF over-expressed BCECs. In vivo multispectral fluorescent imaging, the EGFP-EGF1 conjugated nanoparticles showed significantly higher accumulation in tumor tissues than non-conjugated ones. Tumor tissue slides further presented that EGFP-EGF1 conjugated nanoparticles showed significantly higher accumulation in tumor vasculature than non-conjugated ones. In vitro study demonstrated that PDT increased TF expression of BCECs. In vivo imaging, ex vivo imaging and tumor tissue slides showed that PDT further contribute EGFP-EGF1-NP accumulation in tumor. These promising results indicated that PDT enhanced EGFP-EGF1modified PEG-PLGA nanoparticle accumulation in tumor vaculature. Considering that EGFP-EGF1 conjugation enhanced nanoparticles uptake by TF over-expressed endothelium and PDT increased endothelium TF expression. We conclude that PDT triggered a TF cascade targeted effect. A combination of both EGFP-EGF1 modification and PDT provided a positive feed-back target effect to tumor vessels and might have a great potential for tumor therapy.

Pharmacokinetic drivers of toxicity for basic molecules: Strategy to lower pKa results in decreased tissue exposure and toxicity for a small molecule Met inhibitor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Diaz, Dolores, E-mail: diaz.dolores@gene.com; Ford, Kevin A.; Hartley, Dylan P.

Several toxicities are clearly driven by free drug concentrations in plasma, such as toxicities related to on-target exaggerated pharmacology or off-target pharmacological activity associated with receptors, enzymes or ion channels. However, there are examples in which organ toxicities appear to correlate better with total drug concentrations in the target tissues, rather than with free drug concentrations in plasma. Here we present a case study in which a small molecule Met inhibitor, GEN-203, with significant liver and bone marrow toxicity in preclinical species was modified with the intention of increasing the safety margin. GEN-203 is a lipophilic weak base as demonstratedmore » by its physicochemical and structural properties: high LogD (distribution coefficient) (4.3) and high measured pKa (7.45) due to the basic amine (N-ethyl-3-fluoro-4-aminopiperidine). The physicochemical properties of GEN-203 were hypothesized to drive the high distribution of this compound to tissues as evidenced by a moderately-high volume of distribution (Vd > 3 l/kg) in mouse and subsequent toxicities of the compound. Specifically, the basicity of GEN-203 was decreased through addition of a second fluorine in the 3-position of the aminopiperidine to yield GEN-890 (N-ethyl-3,3-difluoro-4-aminopiperidine), which decreased the volume of distribution of the compound in mouse (Vd = 1.0 l/kg), decreased its tissue drug concentrations and led to decreased toxicity in mice. This strategy suggests that when toxicity is driven by tissue drug concentrations, optimization of the physicochemical parameters that drive tissue distribution can result in decreased drug concentrations in tissues, resulting in lower toxicity and improved safety margins. -- Highlights: ► Lower pKa for a small molecule: reduced tissue drug levels and toxicity. ► New analysis tools to assess electrostatic effects and ionization are presented. ► Chemical and PK drivers of toxicity can be leveraged to improve safety.« less

Tissue distribution of enrofloxacin after intramammary or simulated systemic administration in isolated perfused sheep udders.

PubMed

López Cadenas, Cristina; Fernández Martínez, Nélida; Sierra Vega, Matilde; Diez Liébana, Maria J; Gonzalo Orden, Jose M; Sahagún Prieto, Ana M; García Vieitez, Juan J

2012-11-01

To determine the tissue distribution of enrofloxacin after intramammary or simulated systemic administration in isolated perfused sheep udders by measuring its concentration at various sample collection sites. 26 udders (obtained following euthanasia) from 26 healthy lactating sheep. For each isolated udder, 1 mammary gland was perfused with warmed, gassed Tyrode solution. Enrofloxacin (1 g of enrofloxacin/5 g of ointment) was administered into the perfused gland via the intramammary route or systemically via the perfusion fluid (equivalent to a dose of 5 mg/kg). Samples of the perfusate were obtained every 30 minutes for 180 minutes; glandular tissue samples were obtained at 2, 4, 6, and 8 cm from the teat base after 180 minutes. The enrofloxacin content of the perfusate and tissue samples was analyzed via high-performance liquid chromatography with UV detection. After intramammary administration, maximun perfusate enrofloxacin concentration was detected at 180 minutes and, at this time, mean tissue enrofloxacin concentration was detected and mean tissue enrofloxacin concentration was 123.80, 54.48, 36.72, and 26.42 μg/g of tissue at 2, 4, 6, and 8 cm from the teat base, respectively. Following systemic administration, perfusate enrofloxacin concentration decreased with time and, at 180 minutes, tissue enrofloxacin concentrations ranged from 40.38 to 35.58 μg/g of tissue. By 180 minutes after administration via the intramammary or systemic route in isolated perfused sheep mammary glands, mean tissue concentration of enrofloxacin was greater than the minimum inhibitory concentration required to inhibit growth of 90% of many common mastitis pathogens in sheep. Use of either route of administration (or in combination) appears suitable for the treatment of acute mastitis in sheep.

Oxidized macrophage migration inhibitory factor is a potential new tissue marker and drug target in cancer.

PubMed

Schinagl, Alexander; Thiele, Michael; Douillard, Patrice; Völkel, Dirk; Kenner, Lukas; Kazemi, Zahra; Freissmuth, Michael; Scheiflinger, Friedrich; Kerschbaumer, Randolf J

2016-11-08

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine, which was shown to be upregulated in cancers and to exhibit tumor promoting properties. Unlike other cytokines, MIF is ubiquitously present in the circulation and tissue of healthy subjects. We recently described a previously unrecognized, disease-related isoform of MIF, designated oxMIF, which is present in the circulation of patients with different inflammatory diseases. In this article, we report that oxMIF is also linked to different solid tumors as it is specifically expressed in tumor tissue from patients with colorectal, pancreatic, ovarian and lung cancer. Furthermore, oxMIF can be specifically targeted by a subset of phage display-derived fully human, monoclonal anti-MIF antibodies (mAbs) that were shown to neutralize pro-tumorigenic activities of MIF in vivo. We further demonstrate that anti-oxMIF mAbs sensitize human cancer cell lines (LNCaP, PC3, A2780 and A2780ADR) to the action of cytotoxic drugs (mitoxantrone, cisplatin and doxorubicin) in vitro and in an A2780 xenograft mouse model of ovarian cancer. We conclude that oxMIF is the disease related isoform of MIF in solid tumors and a potential new diagnostic marker and drug target in cancer.

Mechanisms of Vascular Damage by Hemorrhagic Snake Venom Metalloproteinases: Tissue Distribution and In Situ Hydrolysis

PubMed Central

Baldo, Cristiani; Jamora, Colin; Yamanouye, Norma; Zorn, Telma M.; Moura-da-Silva, Ana M.

2010-01-01

Background Envenoming by viper snakes constitutes an important public health problem in Brazil and other developing countries. Local hemorrhage is an important symptom of these accidents and is correlated with the action of snake venom metalloproteinases (SVMPs). The degradation of vascular basement membrane has been proposed as a key event for the capillary vessel disruption. However, SVMPs that present similar catalytic activity towards extracellular matrix proteins differ in their hemorrhagic activity, suggesting that other mechanisms might be contributing to the accumulation of SVMPs at the snakebite area allowing capillary disruption. Methodology/Principal Findings In this work, we compared the tissue distribution and degradation of extracellular matrix proteins induced by jararhagin (highly hemorrhagic SVMP) and BnP1 (weakly hemorrhagic SVMP) using the mouse skin as experimental model. Jararhagin induced strong hemorrhage accompanied by hydrolysis of collagen fibers in the hypodermis and a marked degradation of type IV collagen at the vascular basement membrane. In contrast, BnP1 induced only a mild hemorrhage and did not disrupt collagen fibers or type IV collagen. Injection of Alexa488-labeled jararhagin revealed fluorescent staining around capillary vessels and co-localization with basement membrane type IV collagen. The same distribution pattern was detected with jararhagin-C (disintegrin-like/cysteine-rich domains of jararhagin). In opposition, BnP1 did not accumulate in the tissues. Conclusions/Significance These results show a particular tissue distribution of hemorrhagic toxins accumulating at the basement membrane. This probably occurs through binding to collagens, which are drastically hydrolyzed at the sites of hemorrhagic lesions. Toxin accumulation near blood vessels explains enhanced catalysis of basement membrane components, resulting in the strong hemorrhagic activity of SVMPs. This is a novel mechanism that underlies the difference between

Evaluation of biomolecular distributions in rat brain tissues by means of ToF-SIMS using a continuous beam of Ar clusters.

PubMed

Nakano, Shusuke; Yokoyama, Yuta; Aoyagi, Satoka; Himi, Naoyuki; Fletcher, John S; Lockyer, Nicholas P; Henderson, Alex; Vickerman, John C

2016-06-08

Time-of-flight secondary ion mass spectrometry (ToF-SIMS) provides detailed chemical structure information and high spatial resolution images. Therefore, ToF-SIMS is useful for studying biological phenomena such as ischemia. In this study, in order to evaluate cerebral microinfarction, the distribution of biomolecules generated by ischemia was measured with ToF-SIMS. ToF-SIMS data sets were analyzed by means of multivariate analysis for interpreting complex samples containing unknown information and to obtain biomolecular mapping indicated by fragment ions from the target biomolecules. Using conventional ToF-SIMS (primary ion source: Bi cluster ion), it is difficult to detect secondary ions beyond approximately 1000 u. Moreover, the intensity of secondary ions related to biomolecules is not always high enough for imaging because of low concentration even if the masses are lower than 1000 u. However, for the observation of biomolecular distributions in tissues, it is important to detect low amounts of biological molecules from a particular area of tissue. Rat brain tissue samples were measured with ToF-SIMS (J105, Ionoptika, Ltd., Chandlers Ford, UK), using a continuous beam of Ar clusters as a primary ion source. ToF-SIMS with Ar clusters efficiently detects secondary ions related to biomolecules and larger molecules. Molecules detected by ToF-SIMS were examined by analyzing ToF-SIMS data using multivariate analysis. Microspheres (45 μm diameter) were injected into the rat unilateral internal carotid artery (MS rat) to cause cerebral microinfarction. The rat brain was sliced and then measured with ToF-SIMS. The brain samples of a normal rat and the MS rat were examined to find specific secondary ions related to important biomolecules, and then the difference between them was investigated. Finally, specific secondary ions were found around vessels incorporating microspheres in the MS rat. The results suggest that important biomolecules related to cerebral

Distribution of polycyclic aromatic hydrocarbons in subcellular root tissues of ryegrass (Lolium multiflorum Lam.)

PubMed Central

2010-01-01

Background Because of the increasing quantity and high toxicity to humans of polycyclic aromatic hydrocarbons (PAHs) in the environment, several bioremediation mechanisms and protocols have been investigated to restore PAH-contaminated sites. The transport of organic contaminants among plant cells via tissues and their partition in roots, stalks, and leaves resulting from transpiration and lipid content have been extensively investigated. However, information about PAH distributions in intracellular tissues is lacking, thus limiting the further development of a mechanism-based phytoremediation strategy to improve treatment efficiency. Results Pyrene exhibited higher uptake and was more recalcitrant to metabolism in ryegrass roots than was phenanthrene. The kinetic processes of uptake from ryegrass culture medium revealed that these two PAHs were first adsorbed onto root cell walls, and they then penetrated cell membranes and were distributed in intracellular organelle fractions. At the beginning of uptake (< 50 h), adsorption to cell walls dominated the subcellular partitioning of the PAHs. After 96 h of uptake, the subcellular partition of PAHs approached a stable state in the plant water system, with the proportion of PAH distributed in subcellular fractions being controlled by the lipid contents of each component. Phenanthrene and pyrene primarily accumulated in plant root cell walls and organelles, with about 45% of PAHs in each of these two fractions, and the remainder was retained in the dissolved fraction of the cells. Because of its higher lipophilicity, pyrene displayed greater accumulation factors in subcellular walls and organelle fractions than did phenanthrene. Conclusions Transpiration and the lipid content of root cell fractions are the main drivers of the subcellular partition of PAHs in roots. Initially, PAHs adsorb to plant cell walls, and they then gradually diffuse into subcellular fractions of tissues. The lipid content of intracellular

Pharmacokinetics, tissue distribution, and metabolism of nitrofurantoin in the channel catfish (Ictalurus punctatus)

USGS Publications Warehouse

Stehly, G.R.; Plakas, S.M.

1993-01-01

The pharmacokinetics, tissue distribution, and metabolism of the drug nitrofurantoin were examined in the channel catfish (Ictalurus punctatus) after intravascular or oral dosing. Mean plasma concentrations of nitrofurantoin after intravascular administration at 1 and 10 mg/kg of body weight were best fit to two- and three-compartment pharmacokinetic models, respectively. Nitrofurantoin was rapidly eliminated from the plasma after intravascular dosing; at 1 and 10 mg/kg, the terminal half-lives were 23 and 46 min, respectively. After oral dosing at 1 mg/kg, peak plasma concentrations (0.06 mu g/ml) occurred at 2 h; the bioavailability was 17%. Residues of nitrofurantoin and its metabolites in the tissues were initially eliminated rapidly but persisted at the later sampling times. Residue concentrations were highest in the plasma and excretory tissues. Approximately 21% and 4% of the oral dose were eliminated in the urine and bile, respectively. Parent nitrofurantoin was the major radiolabelled compound found in the urine; however, the percentage of total residues composed of metabolites increased with time. Biliary residues consisted mostly of nitrofurantoin metabolites. High-performance liquid chromatography revealed the presence of at least five metabolites in the urine and bile.

Collecting lymphatic vessel permeability facilitates adipose tissue inflammation and distribution of antigen to lymph node-homing adipose tissue dendritic cells.

PubMed

Kuan, Emma L; Ivanov, Stoyan; Bridenbaugh, Eric A; Victora, Gabriel; Wang, Wei; Childs, Ed W; Platt, Andrew M; Jakubzick, Claudia V; Mason, Robert J; Gashev, Anatoliy A; Nussenzweig, Michel; Swartz, Melody A; Dustin, Michael L; Zawieja, David C; Randolph, Gwendalyn J

2015-06-01

Collecting lymphatic vessels (CLVs), surrounded by fat and endowed with contractile muscle and valves, transport lymph from tissues after it is absorbed into lymphatic capillaries. CLVs are not known to participate in immune responses. In this study, we observed that the inherent permeability of CLVs allowed broad distribution of lymph components within surrounding fat for uptake by adjacent macrophages and dendritic cells (DCs) that actively interacted with CLVs. Endocytosis of lymph-derived Ags by these cells supported recall T cell responses in the fat and also generated Ag-bearing DCs for emigration into adjacent lymph nodes (LNs). Enhanced recruitment of DCs to inflammation-reactive LNs significantly relied on adipose tissue DCs to maintain sufficient numbers of Ag-bearing DCs as the LN expanded. Thus, CLVs coordinate inflammation and immunity within adipose depots and foster the generation of an unexpected pool of APCs for Ag transport into the adjacent LN. Copyright © 2015 by The American Association of Immunologists, Inc.

The Role of Experience in Location Estimation: Target Distributions Shift Location Memory Biases

ERIC Educational Resources Information Center

Lipinski, John; Simmering, Vanessa R.; Johnson, Jeffrey S.; Spencer, John P.

2010-01-01

Research based on the Category Adjustment model concluded that the spatial distribution of target locations does not influence location estimation responses [Huttenlocher, J., Hedges, L., Corrigan, B., & Crawford, L. E. (2004). Spatial categories and the estimation of location. "Cognition, 93", 75-97]. This conflicts with earlier results showing…

Quantitative investigation of the edge enhancement in in-line phase contrast projections and tomosynthesis provided by distributing microbubbles on the interface between two tissues: a phantom study

NASA Astrophysics Data System (ADS)

Wu, Di; Donovan Wong, Molly; Li, Yuhua; Fajardo, Laurie; Zheng, Bin; Wu, Xizeng; Liu, Hong

2017-12-01

The objective of this study was to quantitatively investigate the ability to distribute microbubbles along the interface between two tissues, in an effort to improve the edge and/or boundary features in phase contrast imaging. The experiments were conducted by employing a custom designed tissue simulating phantom, which also simulated a clinical condition where the ligand-targeted microbubbles are self-aggregated on the endothelium of blood vessels surrounding malignant cells. Four different concentrations of microbubble suspensions were injected into the phantom: 0%, 0.1%, 0.2%, and 0.4%. A time delay of 5 min was implemented before image acquisition to allow the microbubbles to become distributed at the interface between the acrylic and the cavity simulating a blood vessel segment. For comparison purposes, images were acquired using three system configurations for both projection and tomosynthesis imaging with a fixed radiation dose delivery: conventional low-energy contact mode, low-energy in-line phase contrast and high-energy in-line phase contrast. The resultant images illustrate the edge feature enhancements in the in-line phase contrast imaging mode when the microbubble concentration is extremely low. The quantitative edge-enhancement-to-noise ratio calculations not only agree with the direct image observations, but also indicate that the edge feature enhancement can be improved by increasing the microbubble concentration. In addition, high-energy in-line phase contrast imaging provided better performance in detecting low-concentration microbubble distributions.

Dosimetric comparison between VMAT with different dose calculation algorithms and protons for soft-tissue sarcoma radiotherapy.

PubMed

Fogliata, Antonella; Scorsetti, Marta; Navarria, Piera; Catalano, Maddalena; Clivio, Alessandro; Cozzi, Luca; Lobefalo, Francesca; Nicolini, Giorgia; Palumbo, Valentina; Pellegrini, Chiara; Reggiori, Giacomo; Roggio, Antonella; Vanetti, Eugenio; Alongi, Filippo; Pentimalli, Sara; Mancosu, Pietro

2013-04-01

To appraise the potential of volumetric modulated arc therapy (VMAT, RapidArc) and proton beams to simultaneously achieve target coverage and enhanced sparing of bone tissue in the treatment of soft-tissue sarcoma with adequate target coverage. Ten patients presenting with soft-tissue sarcoma of the leg were collected for the study. Dose was prescribed to 66.5 Gy in 25 fractions to the planning target volume (PTV) while significant maximum dose to the bone was constrained to 50 Gy. Plans were optimised according to the RapidArc technique with 6 MV photon beams or for intensity modulated protons. RapidArc photon plans were computed with: 1) AAA; 2) Acuros XB as dose to medium; and 3) Acuros XB as dose to water. All plans acceptably met the criteria of target coverage (V95% >90-95%) and bone sparing (D(1 cm3) <50 Gy). Significantly higher PTV dose homogeneity was found for proton plans. Near-to-maximum dose to bone was similar for RapidArc and protons, while volume receiving medium/low dose levels was minimised with protons. Similar results were obtained for the remaining normal tissue. Dose distributions calculated with the dose to water option resulted ~5% higher than corresponding ones computed as dose to medium. High plan quality was demonstrated for both VMAT and proton techniques when applied to soft-tissue sarcoma.

Multimodal assessment of spatial distribution of drug-tracer uptake by brain tissue after intra-arterial injections

NASA Astrophysics Data System (ADS)

Singh-Moon, Rajinder; Chaudhuri, Durba; Wang, Mei; Straubinger, Robert; Bigio, Irving J.; Joshi, Shailendra

2014-02-01

It is challenging to track the rapid changes in drug concentrations after intra-arterial (IA) administration to elucidate the pharmacokinetics of this method of drug delivery. Traditional pharmacokinetic parameters (such as protein binding) that are highly relevant to intravenous (IV) administration do not seem to apply to IA injections. Regional drug delivery is affected by the biomechanics of drug injection, resting blood flow, and local tissue extraction. In-vivo and ex-vivo, optical methods for spatial mapping of drug deposition can assist in visualizing drug distributions and aid in the screening of potential drugs and carrier candidates. We present a multimodal approach for the assessment of drug distribution in postmortem tissue specimens using diffuse reflectance spectroscopy, multispectral imaging, and confocal microscopy and demonstrate feasibility of distinguishing route of administration advantages of liposome-dye conjugate delivery. The results of this study suggest that insight on drug dynamics gained by this aggregated approach can be used to help screen and/or optimize potential drug candidates and drug delivery protocols.

Duragesic transdermal patch: postmortem tissue distribution of fentanyl in 25 cases.

PubMed

Anderson, D T; Muto, J J

2000-10-01

Fentanyl is a potent, short-acting narcotic analgesic widely used as a surgical anesthetic and for the control of pain when administered in the form of a transdermal patch. The success of the patch can be attributed to fentanyl's low molecular weight and its highly lipophilic nature, which enables it to be readily absorbed through the skin and subsequently distributed throughout the body. Over the past three years, the Los Angeles County Coroner's Toxicology Laboratory has encountered 25 cases involving Duragesic patches (fentanyl), and their postmortem tissue distributions are presented here. The analysis of fentanyl from postmortem specimens (3-mL or g sample size) consisted of an n-butyl chloride basic extraction followed by identification and quantitation on a gas chromatograph-mass spectrometer using the selected ion monitoring (SIM) mode. The fentanyl ions monitored were m/z 245, 146, and 189 and the internal standard, fentanyl-d5 ions, were m/z 250, 151, and 194 (quantitation ion underlined). The linear range of the assay was 1.67 microg/L to 500 microg/L with the limit of quantitation and detection of 1.67 microg/L. The postmortem tissue distribution ranges of fentanyl in the 25 fatalities were as follows: heart blood, 1.8-139 microg/L (23 cases); femoral blood, 3.1-43 microg/L (13 cases); vitreous, +<2.0-20 microg/L (4 cases); liver, 5.8-613 microg/kg (22 cases); bile, 3.5-262 microg/L (15 cases); urine, 2.9-895 microg/L (19 cases); gastric, 0-1200 microg total (17 cases); spleen, 7.8-79 microg/kg (3 cases); kidney, 11 microg/kg (1 case); and lung, 31 microg/kg (1 case). The age of the decedents in this study ranged from 19 to 84, with an average age of 46. The modes of death included 15 accidental, 5 natural, 3 suicidal, and 2 undetermined. The main objectives of this paper are to show the prevalence of fentanyl patches in our community and to aid the forensic toxicologist with the interpretation of postmortem fentanyl levels in casework.

Maternal transfer of dechloranes and their distribution among tissues in contaminated ducks.

PubMed

Wu, Ping-Fan; Yu, Lian-Lian; Li, Long; Zhang, Yun; Li, Xing-Hong

2016-05-01

The tissue concentrations of dechlorane plus and its analogues were determined in ducks collected from several e-waste recycling villages of Taizhou, China. Compared with the published literature, the relatively high concentrations of these compounds were detected in ducks, indicating serious DP contamination. Since both the duck meat and eggs were important components for diet, this result reminded us of keeping a watchful eye on human dietary exposure to DP and its analogues in this study area. The wet-weight concentrations of DP and its analogues were significantly related to tissue lipid content (p < 0.05), indicating that the lipid pools predominantly impacted the distribution of DPs in ducks. On the basis of lipid adjustment, the significantly lower levels in brain than those in liver and blood, displayed the occurrence of liver sequestration and blood-brain barrier to DP and its analogues in the duck (p < 0.05). The maternal transfer of DP and Mirex was not obviously limited, and the transferring extent of Dec 602 was over one. The stereo-selected accumulation of two DP isomers occurred among tissues with preference to syn-DP in blood, and to anti-DP in brain. The values of lipid-adjusted monodechlorinated products mainly originated from the exterior environment in ducks. Copyright © 2015 Elsevier Ltd. All rights reserved.

Tracking of multimodal therapeutic nanocomplexes targeting breast cancer in vivo.

PubMed

Bardhan, Rizia; Chen, Wenxue; Bartels, Marc; Perez-Torres, Carlos; Botero, Maria F; McAninch, Robin Ward; Contreras, Alejandro; Schiff, Rachel; Pautler, Robia G; Halas, Naomi J; Joshi, Amit

2010-12-08

Nanoparticle-based therapeutics with local delivery and external electromagnetic field modulation holds extraordinary promise for soft-tissue cancers such as breast cancer; however, knowledge of the distribution and fate of nanoparticles in vivo is crucial for clinical translation. Here we demonstrate that multiple diagnostic capabilities can be introduced in photothermal therapeutic nanocomplexes by simultaneously enhancing both near-infrared fluorescence and magnetic resonance imaging (MRI). We track nanocomplexes in vivo, examining the influence of HER2 antibody targeting on nanocomplex distribution over 72 h. This approach provides valuable, detailed information regarding the distribution and fate of complex nanoparticles designed for specific diagnostic and therapeutic functions.

Tracking of Multimodal Therapeutic Nanocomplexes Targeting Breast Cancer in Vivo

PubMed Central

Bardhan, Rizia; Chen, Wenxue; Bartels, Marc; Perez-Torres, Carlos; Botero, Maria F.; McAninch, Robin Ward; Contreras, Alejandro; Schiff, Rachel; Pautler, Robia G.; Halas, Naomi J.; Joshi, Amit

2014-01-01

Nanoparticle-based therapeutics with local delivery and external electromagnetic field modulation holds extraordinary promise for soft-tissue cancers such as breast cancer; however, knowledge of the distribution and fate of nanoparticles in vivo is crucial for clinical translation. Here we demonstrate that multiple diagnostic capabilities can be introduced in photothermal therapeutic nanocomplexes by simultaneously enhancing both near-infrared fluorescence and magnetic resonance imaging (MRI). We track nanocomplexes in vivo, examining the influence of HER2 antibody targeting on nanocomplex distribution over 72 h. This approach provides valuable, detailed information regarding the distribution and fate of complex nanoparticles designed for specific diagnostic and therapeutic functions. PMID:21090693

Experimental Retrieval of Target Structure Information from Laser-Induced Rescattered Photoelectron Momentum Distributions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Okunishi, M.; Pruemper, G.; Shimada, K.

We have measured two-dimensional photoelectron momentum spectra of Ne, Ar, and Xe generated by 800-nm, 100-fs laser pulses and succeeded in identifying the spectral ridge region (back-rescattered ridges) which marks the location of the returning electrons that have been backscattered at their maximum kinetic energies. We demonstrate that the structural information, in particular the differential elastic scattering cross sections of the target ion by free electrons, can be accurately extracted from the intensity distributions of photoelectrons on the ridges, thus effecting a first step toward laser-induced self-imaging of the target, with unprecedented spatial and temporal resolutions.

Tissue distribution in mice of BPP 10c, a potent proline-rich anti-hypertensive peptide of Bothrops jararaca.

PubMed

Silva, Carlos A; Portaro, Fernanda C V; Fernandes, Beatriz L; Ianzer, Danielle A; Guerreiro, Juliano R; Gomes, Claudiana L; Konno, Katsuhiro; Serrano, Solange M T; Nascimento, Nanci; Camargo, Antonio C M

2008-03-15

The snake venom proline-rich peptide BPP 10c is an active somatic angiotensin-converting enzyme (sACE) inhibitors. Recently we demonstrated that the anti-hypertensive effect of BPP 10c is not related to the inhibition of sACE alone, thus suggesting that this enzyme is not its only target for blood pressure reduction. In the present work, a biodistribution study in Swiss mice of [(125)I]-BPP 10c in the absence or in the presence of a saturating concentration of captopril, a selective active-site inhibitor of sACE, demonstrated that: (1) [(125)I]-BPP 10c was present in several organs and the renal absorption was significantly high; (2) [(125)I]-BPP 10c showed a clear preference for the kidney, maintaining a high concentration in this organ in the presence of captopril for at least 3h; (3) The residual amount of [(125)I]-BPP 10c in the kidney of animals simultaneously treated with captopril suggest that the peptide can interact with other targets different from sACE in this organ. We also showed that Cy3-labeled BPP 10c was internalized by human embryonic kidney cells (HEK-293T). Taken together, these results suggest that sACE inhibition by captopril affects the tissue distribution of [(125)I]-BPP 10c and that the anti-hypertensive effects of BPP 10c are not only dependent on sACE inhibition.

Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.

PubMed

Baar, Marjolein P; Brandt, Renata M C; Putavet, Diana A; Klein, Julian D D; Derks, Kasper W J; Bourgeois, Benjamin R M; Stryeck, Sarah; Rijksen, Yvonne; van Willigenburg, Hester; Feijtel, Danny A; van der Pluijm, Ingrid; Essers, Jeroen; van Cappellen, Wiggert A; van IJcken, Wilfred F; Houtsmuller, Adriaan B; Pothof, Joris; de Bruin, Ron W F; Madl, Tobias; Hoeijmakers, Jan H J; Campisi, Judith; de Keizer, Peter L J

2017-03-23

The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density, and renal function in both fast aging Xpd TTD/TTD and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored. Copyright © 2017 Elsevier Inc. All rights reserved.

Synovial tissue volume: a treatment target in knee osteoarthritis (OA).

PubMed

O'Neill, Terence W; Parkes, Matthew J; Maricar, Nasimah; Marjanovic, Elizabeth J; Hodgson, Richard; Gait, Andrew D; Cootes, Timothy F; Hutchinson, Charles E; Felson, David T

2016-01-01

Synovitis occurring frequently in osteoarthritis (OA) may be a targeted outcome. There are no data examining whether synovitis changes following intra-articular intervention. Persons aged 40 years and older with painful knee OA participated in an open label trial of intra-articular steroid therapy. At all time points they completed the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. They had a contrast-enhanced (CE) MRI immediately prior to an intra-articular steroid injection with a repeat scan within 20 days. Response status was assessed using the Osteoarthritis Research Society International (OARSI) response criteria. OARSI responders were followed until their pain relapsed either within 20% of baseline or 6 months, shortly after which a third MRI was performed. Synovial tissue volume (STV) was measured on postcontrast knee images. We looked at changes in the STV and in pain, and their association. 120 subjects with preinjection and postinjection CE MRI were followed. Their mean age was 62.3 years (SD=10.3) and 62 (52%) were women. The median time between injection and follow-up scan was 8 days (IQR 7-14 days). 85/120 (71%) were OARSI responders. Pain decreased (mean change in KOOS=+23.9; 95% CI 20.1 to 27.8, p<0.001) following steroid injection, as did mean STV (mean change=-1071 mm(3); 95% CI -1839 mm(3) to -303 mm(3), p=0.01). Of the 80 who returned for a third MRI, pain relapsed in 57, and in the 48 of those with MRI data, STV increased between follow-up and final visit (+1220 mm(3); 95% CI 25 mm(3) to 2414 mm(3), p=0.05). 23 were persistent responders at 6 months and, in these, STV did not increase (mean change=-202 mm(3); 95% CI -2008 mm(3) to 1604 mm(3), p=0.83). Controlling for variation over time, there was a significant association between synovitis volume and KOOS pain (b coefficient-change in KOOS pain score per 1000 mm(3) change in STV=-1.13; 95% CI -1.87 to -0.39, p=0.003), although STV accounted for only a small proportion of

Cyclin Dependent Kinase Inhibitors as Targets in Ovarian Cancer

DTIC Science & Technology

2005-10-01

STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT The objective of this proposal is to develop gene ...have identified key genes that may be effective targets in ovarian cancer therapy. The first three projects seek to identify alterations in these genes ...that allow for high expression of our key gene (s) in ovarian cancer cells but minimal expression in normal tissues. 15. SUBJECT TERMS Cell cycle control

Comparative pharmacokinetic and tissue distribution profiles of four major bioactive components in normal and hepatic fibrosis rats after oral administration of Fuzheng Huayu recipe.

PubMed

Yang, Tao; Liu, Shan; Wang, Chang-Hong; Tao, Yan-Yan; Zhou, Hua; Liu, Cheng-Hai

2015-10-10

Fuzheng Huayu recipe (FZHY) is a herbal product for the treatment of liver fibrosis approved by the Chinese State Food and Drug Administration (SFDA), but its pharmacokinetics and tissue distribution had not been investigated. In this study, the liver fibrotic model was induced with intraperitoneal injection of dimethylnitrosamine (DMN), and FZHY was given orally to the model and normal rats. The plasma pharmacokinetics and tissue distribution profiles of four major bioactive components from FZHY were analyzed in the normal and fibrotic rat groups using an ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method. Results revealed that the bioavailabilities of danshensu (DSS), salvianolic acid B (SAB) and rosmarinic acid (ROS) in liver fibrotic rats increased 1.49, 3.31 and 2.37-fold, respectively, compared to normal rats. There was no obvious difference in the pharmacokinetics of amygdalin (AMY) between the normal and fibrotic rats. The tissue distribution of DSS, SAB, and AMY trended to be mostly in the kidney and lung. The distribution of DSS, SAB, and AMY in liver tissue of the model rats was significantly decreased compared to the normal rats. Significant differences in the pharmacokinetics and tissue distribution profiles of DSS, ROS, SAB and AMY were observed in rats with hepatic fibrosis after oral administration of FZHY. These results provide a meaningful basis for developing a clinical dosage regimen in the treatment of hepatic fibrosis by FZHY. Copyright © 2015 Elsevier B.V. All rights reserved.

Tissue Expanders and Proton Beam Radiotherapy: What You Need to Know

PubMed Central

Howarth, Ashley L.; Niska, Joshua R.; Brooks, Kenneth; Anand, Aman; Bues, Martin; Vargas, Carlos E.

2017-01-01

Summary: Proton beam radiotherapy (PBR) has gained acceptance for the treatment of breast cancer because of unique beam characteristics that allow superior dose distributions with optimal dose to the target and limited collateral damage to adjacent normal tissue, especially to the heart and lungs. To determine the compatibility of breast tissue expanders (TEs) with PBR, we evaluated the structural and dosimetric properties of 2 ex vivo models: 1 model with internal struts and another model without an internal structure. Although the struts appeared to have minimal impact, we found that the metal TE port alters PBR dynamics, which may increase proton beam range uncertainty. Therefore, submuscular TE placement may be preferable to subcutaneous TE placement to reduce the interaction of the TE and proton beam. This will reduce range uncertainty and allow for more ideal radiation dose distribution. PMID:28740794

A comparison of the energy distributions of hadrons produced in deep inelastic scattering of muons on hydrogen and deuterium targets

NASA Astrophysics Data System (ADS)

Aubert, J. J.; Bassompierre, G.; Becks, K. H.; Benchouk, C.; Best, C.; Böhm, E.; de Bouard, X.; Brasse, F. W.; Broll, C.; Brown, S.; Carr, J.; Clifft, R.; Cobb, J. H.; Coignet, G.; Combley, F.; Court, G. R.; D'Agostini, G.; Dau, W. D.; Davies, J. K.; Déclais, Y.; Dosselli, U.; Drees, J.; Edwards, A.; Edwards, M.; Eszes, G.; Favier, J.; Ferrero, M. I.; Flauger, W.; Forsbach, H.; Gabathuler, E.; Gamet, R.; Gayler, J.; Gerhardt, V.; Gössling, C.; Haas, J.; Hamacher, K.; Hayman, P.; Henckes, M.; Korbel, V.; Korzen, B.; Landgraf, U.; Leenen, M.; Maire, M.; Mohr, W.; Montgomery, H. E.; Moser, K.; Mount, R. P.; Nagy, E.; Nassalski, J.; Norton, P. R.; McNicholas, J.; Osborne, A. M.; Pavel, N.; Payre, P.; Peroni, C.; Peschel, H.; Pessard, H.; Pietrzyk, U.; Ribarics, P.; Rith, K.; Schneegans, M.; Schneider, A.; Sloan, T.; Stier, H. E.; Stockhausen, W.; Thénard, J. M.; Thompson, J. C.; Urban, L.; Villers, M.; Wahlen, H.; Whalley, M.; Williams, D.; Williams, W. S. C.; Williamson, J.; Wimpenny, S. J.

1986-06-01

The energy distribution of inclusive hadrons produced by 280 GeV muons on hydrogen and deuterium targets are compared. The sum of the scaled energy distributions of the positive and negative hadrons is found to be the same for the two targets. The difference of these distributions is observed to factorise in x and z and the z-dependence is found to be independent of the target type and have a form (1- z)2.1±0.2. The net charge of the hadronic jet is positive at high x even in the case when the scattering takes place on the neutron. These results are in good agreement with the expectations of the Quark Parton Model.

Multichannel imaging to quantify four classes of pharmacokinetic distribution in tumors.

PubMed

Bhatnagar, Sumit; Deschenes, Emily; Liao, Jianshan; Cilliers, Cornelius; Thurber, Greg M

2014-10-01

Low and heterogeneous delivery of drugs and imaging agents to tumors results in decreased efficacy and poor imaging results. Systemic delivery involves a complex interplay of drug properties and physiological factors, and heterogeneity in the tumor microenvironment makes predicting and overcoming these limitations exceptionally difficult. Theoretical models have indicated that there are four different classes of pharmacokinetic behavior in tissue, depending on the fundamental steps in distribution. In order to study these limiting behaviors, we used multichannel fluorescence microscopy and stitching of high-resolution images to examine the distribution of four agents in the same tumor microenvironment. A validated generic partial differential equation model with a graphical user interface was used to select fluorescent agents exhibiting these four classes of behavior, and the imaging results agreed with predictions. BODIPY-FL exhibited higher concentrations in tissue with high blood flow, cetuximab gave perivascular distribution limited by permeability, high plasma protein and target binding resulted in diffusion-limited distribution for Hoechst 33342, and Integrisense 680 was limited by the number of binding sites in the tissue. Together, the probes and simulations can be used to investigate distribution in other tumor models, predict tumor drug distribution profiles, and design and interpret in vivo experiments. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Multichannel imaging to quantify four classes of pharmacokinetic distribution in tumors

PubMed Central

Bhatnagar, Sumit; Deschenes, Emily; Liao, Jianshan; Cilliers, Cornelius; Thurber, Greg M.

2014-01-01

Low and heterogeneous delivery of drugs and imaging agents to tumors results in decreased efficacy and poor imaging results. Systemic delivery involves a complex interplay of drug properties and physiological factors, and heterogeneity in the tumor microenvironment makes predicting and overcoming these limitations exceptionally difficult. Theoretical models have indicated that there are four different classes of pharmacokinetic behavior in tissue, depending on the fundamental steps in distribution. In order to study these limiting behaviors, we used multichannel fluorescence microscopy and stitching of high-resolution images to examine the distribution of four agents in the same tumor microenvironment. A validated generic partial differential equation model with a graphical user interface was used to select fluorescent agents exhibiting these four classes of behavior, and the imaging results agreed with predictions. BODIPY-FL exhibited higher concentrations in tissue with high blood flow, cetuximab gave perivascular distribution limited by permeability, high plasma protein and target binding resulted in diffusion-limited distribution for Hoechst 33342, and Integrisense 680 was limited by the number of binding sites in the tissue. Together, the probes and simulations can be used to investigate distribution in other tumor models, predict tumor drug distribution profiles, and design and interpret in vivo experiments. PMID:25048378

Distribution pattern and reduction of polychlorinated biphenyls (PCB) in bluefish fillets through adipose tissue removal

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sanders, M.; Haynes, B.L.

1988-11-01

Bluefish, Pomatomus saltatrix, a migratory pelagic species of fish usually travel in large groups of like size along the Atlantic coast. Bluefish of all sizes are caught both commercially and recreationally for human consumption. Owing to its predacious nature, bluefish feed throughout the water column on a large variety of smaller fish and invertebrates. Bluefish bioaccumulate contaminants such as polychlorinated biphenyls (PCB) into various adipose tissues from the water column and through the marine food chain. Two recent reports concluded that PCB concentrations for all except some of the large bluefish caught along the Atlantic coast fell below the limitmore » of 2 ..mu..g/g set by FDA. The purpose of this study was to observe the distribution pattern of PCB in the various edible tissues. Further, it was to determine if the removal of adipose tissues would result in reduced PCB level and therefore decrease PCB exposure to the consumer.« less

Pharmacokinetics and tissue distribution study of Praeruptorin D from Radix peucedani in rats by high-performance liquid chromatography (HPLC).

PubMed

Liang, Taigang; Yue, Wenyan; Du, Xue; Ren, Luhui; Li, Qingshan

2012-01-01

Praeruptorin D (PD), a major pyranocoumarin isolated from Radix Peucedani, exhibited antitumor and anti-inflammatory activities. The aim of this study was to investigate the pharmacokinetics and tissue distribution of PD in rats following intravenous (i.v.) administration. The levels of PD in plasma and tissues were measured by a simple and sensitive reversed-phase high-performance liquid chromatography (HPLC) method. The biosamples were treated by liquid-liquid extraction (LLE) with methyl tert-butyl ether (MTBE) and osthole was used as the internal standard (IS). The chromatographic separation was accomplished on a reversed-phase C(18) column using methanol-water (75:25, v/v) as mobile phase at a flow rate of 0.8 mL/min and ultraviolet detection wave length was set at 323 nm. The results demonstrate that this method has excellent specificity, linearity, precision, accuracy and recovery. The pharmacokinetic study found that PD fitted well into a two-compartment model with a fast distribution phase and a relative slow elimination phase. Tissue distribution showed that the highest concentration was observed in the lung, followed by heart, liver and kidney. Furthermore, PD can also be detected in the brain, which indicated that PD could cross the blood-brain barrier after i.v. administration.

Simultaneous determination of ten Aconitum alkaloids in rat tissues by UHPLC-MS/MS and its application to a tissue distribution study on the compatibility of Heishunpian and Fritillariae thunbergii Bulbus.

PubMed

Yang, Bin; Xu, Yanyan; Wu, Yuanyuan; Wu, Huanyu; Wang, Yuan; Yuan, Lei; Xie, Jiabin; Li, Yubo; Zhang, Yanjun

2016-10-15

A rapid, sensitive and selective ultra-high performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for simultaneous determination of ten Aconitum alkaloids in rat tissues. The tissue samples were prepared by a simple procedure protein precipitation with acetonitrile containing 0.1% acetic acid and separated on an Agilent XDB C18 column (4.6 mm×50mm, 1.8μm) using gradient elution with a mobile phase consisting of water and acetonitrile (both containing 0.1% formic acid) at a flow rate of 0.3mL/min. The quantitive determination was performed on an electrospray ionization (ESI) triple quadrupole tandem mass spectrometer using selective reaction monitoring (SRM) under positive ionization mode. The established method was fully validated according to the USA Food and Drug Administration (FDA) bioanalytical method validation guidance and the results demonstrated that the method was sensitive and selective with the lowest limits of quantification (LLOQ) at 0.025ng/mL in rat tissue homogenates. Meanwhile, the linearity, precision, accuracy, extraction recovery, matrix effect and stability were all within the required limits of biological sample analysis. After method validation, the validated method was successfully applied to the tissue distribution study on the compatibility of Heishunpian (HSP, the processed product of Aconitum carmichaelii Debx) and Fritillariae thunbergii Bulbus (Zhebeimu, ZBM). The results indicated that the distribution feature of monoester diterpenoid aconitines (MDAs), diester diterpenoid aconitines (DDAs) and non-ester alkaloids (NEAs) were inconsistency, and the compatibility of HSP and ZBM resulted in the distribution amount of DDAs increased in tissues. What's more, the results could provide the reliable basis for systematic research on the substance foundation of the compatibility of the herbal pair. Copyright © 2016 Elsevier B.V. All rights reserved.

Psoriasis Skin Inflammation-Induced microRNA-26b Targets NCEH1 in Underlying Subcutaneous Adipose Tissue.

PubMed

Cheung, Louisa; Fisher, Rachel M; Kuzmina, Natalia; Li, Dongqing; Li, Xi; Werngren, Olivera; Blomqvist, Lennart; Ståhle, Mona; Landén, Ning Xu

2016-03-01

Psoriasis is an immune-mediated inflammatory disease, which is associated with a high risk of developing systemic comorbidities, such as obesity, cardiovascular disease, and diabetes mellitus. However, the mechanistic links between psoriatic skin inflammation and systemic comorbidities remain largely unknown. MicroRNAs (miRNAs) are recently discovered gene regulators that play important roles in psoriasis skin inflammation. In this study we aimed to explore whether the skin inflammation in psoriasis affects miRNA expression of the underlying subcutaneous adipose tissue and whether this may be a link between psoriasis and comorbidities. To this end, we compared the miRNA expression profile of subcutaneous adipose tissue underneath lesional and nonlesional psoriatic skin. We further validated the differential expression of several miRNAs and characterized their expression patterns in different cell types present in subcutaneous adipose tissue. We focused on miR-26b-5p, which was highly up-regulated in subcutaneous adipose tissue underneath lesional psoriasis skin. We showed that it targets and down-regulates neutral cholesterol ester hydrolase 1, an enzyme essential for cholesterol efflux, in monocytes/macrophages, adipocytes, vascular endothelial cells, and fibroblasts. We conclude that this miRNA may serve as a mechanistic link between psoriatic skin inflammation and its systemic comorbidities. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Observation the Distribution of Titanium Dioxide Nano-particles in an Experimental Tumor Tissue by a Raman Microscope

NASA Astrophysics Data System (ADS)

Bibin, Andriana B.; Kume, Kyo; Tsutumi, Kotaro; Fukunaga, Yukihiro; Ito, Shinnji; Imamura, Yoshiaki; Miyoshi, Norio

2011-12-01

One of the most important technologies of the 21st century is nanotechnology. Many researchers will have been focusing to employ nanotechnology for medical purpose. Our team was interested in focusing to the application of titanium dioxide (TiO2), as nano-particles, for medical purpose especially drug delivery for the cancer and tumor. The administrations of TiO2 nano-particle via the oral administration of the interface layer particles into the mouse transplanted squamous-cell-carcinoma (SCC) have already conducted. Histology study and Raman spectroscope data were applied to the serial section of frozen tumor tissue in order to observe the distribution of TiO2 nano-particle within the SCC tissue. We used near infrared laser Raman microscopy system, the wavelength is 785 nm. Hematoxyline & eosin stained image and the Raman microscopy system were also used for analyzing the photodynamic therapy (PDT) with 5-ALA and TiO2-particle-sol [TiO2]-ALA-treated tumor samples. As the result, we demonstrated the distribution of TiO2, where TiO2 particles were detected to be distributed in the blood vessel at the bleeding in the SCC tumor tissue. PDT with TiO2 nano-particles that is presented in the SCC-transplanted mouse tumor model can cause the enhancement of photodynamic reaction by nano-particles. Therefore, the combinations of PDT with TiO2 nano-particles may have a possibility to be introduced to the human body in near future for diagnose and PDT treatment of the tumor.

Distribution, Metabolism and Toxic Effects of Beta-Cypermethrin in Lizards (Eremias argus) Following Oral Administration.

PubMed

Chen, Li; Xu, Peng; Diao, Jinling; Di, Shanshan; Li, Ruiting; Zhou, Zhiqiang

2016-04-05

Beta-cypermethrin (BCYP), a synthetic pyrethriod (PYR) pesticide which is a mixture of the alpha- and theta- cypermethrin, have been reported various toxicological profiles to non-target organisms. But little is known about assimilation, accumulation and toxic effects of BCYP in reptiles. The present study firstly elucidated absorption, tissue distribution, excretion of BCYP in Eremias argus . Treated group were administered orally with BCYP 20mg/kg body weight (bw) dissolved in corn oil. Neurotoxicity was observed at 24h after gavage, and the poisoning symptom ameliorated at 72h. The changes of BCYP concentration depended on degradation time and tissues. Lizards had a strong capacity to eliminate BCYP with different tissue distribution. The tissues concentration of BCYP from high to low were intestine, stomach, heart, kidney, blood, lung, liver and brain. Bimodal phenomena were observed in lung, liver and kidney. These results may be due to the activities of enzymes, circadian rhythm, and enterohepatic circulation in lizards. Based on the results of organ coefficient and histopathology analysis in liver, the liver was confirmed as the main target organ. Copyright © 2015 Elsevier B.V. All rights reserved.

Isolating specific cell and tissue compartments from 3D images for quantitative regional distribution analysis using novel computer algorithms.

PubMed

Fenrich, Keith K; Zhao, Ethan Y; Wei, Yuan; Garg, Anirudh; Rose, P Ken

2014-04-15

Isolating specific cellular and tissue compartments from 3D image stacks for quantitative distribution analysis is crucial for understanding cellular and tissue physiology under normal and pathological conditions. Current approaches are limited because they are designed to map the distributions of synapses onto the dendrites of stained neurons and/or require specific proprietary software packages for their implementation. To overcome these obstacles, we developed algorithms to Grow and Shrink Volumes of Interest (GSVI) to isolate specific cellular and tissue compartments from 3D image stacks for quantitative analysis and incorporated these algorithms into a user-friendly computer program that is open source and downloadable at no cost. The GSVI algorithm was used to isolate perivascular regions in the cortex of live animals and cell membrane regions of stained spinal motoneurons in histological sections. We tracked the real-time, intravital biodistribution of injected fluorophores with sub-cellular resolution from the vascular lumen to the perivascular and parenchymal space following a vascular microlesion, and mapped the precise distributions of membrane-associated KCC2 and gephyrin immunolabeling in dendritic and somatic regions of spinal motoneurons. Compared to existing approaches, the GSVI approach is specifically designed for isolating perivascular regions and membrane-associated regions for quantitative analysis, is user-friendly, and free. The GSVI algorithm is useful to quantify regional differences of stained biomarkers (e.g., cell membrane-associated channels) in relation to cell functions, and the effects of therapeutic strategies on the redistributions of biomolecules, drugs, and cells in diseased or injured tissues. Copyright © 2014 Elsevier B.V. All rights reserved.

Pharmacokinetics and tissue distribution of five active ingredients of Eucommiae cortex in normal and ovariectomized mice by UHPLC-MS/MS.

PubMed

An, Jing; Hu, Fangdi; Wang, Changhong; Zhang, Zijia; Yang, Li; Wang, Zhengtao

2016-09-01

1. Pinoresinol di-O-β-d-glucopyranoside (PDG), geniposide (GE), geniposidic acid (GA), aucubin (AN) and chlorogenic acid (CA) are the representative active ingredients in Eucommiae cortex (EC), which may be estrogenic. 2. The ultra high-performance liquid chromatography/tandem mass spectrometry (UHPLC-MS/MS) method for simultaneous determination of the five ingredients showed good linearity, low limits of quantification and high extraction recoveries, as well as acceptable precision, accuracy and stability in mice plasma and tissue samples (liver, spleen, kidney and uterus). It was successfully applied to the comparative study on pharmacokinetics and tissue distribution of PDG, GE, GA, AN and CA between normal and ovariectomized (OVX) mice. 3. The results indicated that except CA, the plasma and tissue concentrations of PDG, GE, GA in OVX mice were all greater than those in normal mice. AN could only be detected in the plasma and liver homogenate of normal mice, which was poorly absorbed in OVX mice and low in other measured tissues. PDG, GE and GA seem to be better absorbed in OVX mice than in normal mice proved by the remarkable increased value of AUC0-∞ and Cmax. It is beneficial that PDG, GE, GA have better plasma absorption and tissue distribution in pathological state.

Distributed Bees Algorithm Parameters Optimization for a Cost Efficient Target Allocation in Swarms of Robots

PubMed Central

Jevtić, Aleksandar; Gutiérrez, Álvaro

2011-01-01

Swarms of robots can use their sensing abilities to explore unknown environments and deploy on sites of interest. In this task, a large number of robots is more effective than a single unit because of their ability to quickly cover the area. However, the coordination of large teams of robots is not an easy problem, especially when the resources for the deployment are limited. In this paper, the Distributed Bees Algorithm (DBA), previously proposed by the authors, is optimized and applied to distributed target allocation in swarms of robots. Improved target allocation in terms of deployment cost efficiency is achieved through optimization of the DBA’s control parameters by means of a Genetic Algorithm. Experimental results show that with the optimized set of parameters, the deployment cost measured as the average distance traveled by the robots is reduced. The cost-efficient deployment is in some cases achieved at the expense of increased robots’ distribution error. Nevertheless, the proposed approach allows the swarm to adapt to the operating conditions when available resources are scarce. PMID:22346677

Three-dimensional modeling and quantitative analysis of gap junction distributions in cardiac tissue.

PubMed

Lackey, Daniel P; Carruth, Eric D; Lasher, Richard A; Boenisch, Jan; Sachse, Frank B; Hitchcock, Robert W

2011-11-01

Gap junctions play a fundamental role in intercellular communication in cardiac tissue. Various types of heart disease including hypertrophy and ischemia are associated with alterations of the spatial arrangement of gap junctions. Previous studies applied two-dimensional optical and electron-microscopy to visualize gap junction arrangements. In normal cardiomyocytes, gap junctions were primarily found at cell ends, but can be found also in more central regions. In this study, we extended these approaches toward three-dimensional reconstruction of gap junction distributions based on high-resolution scanning confocal microscopy and image processing. We developed methods for quantitative characterization of gap junction distributions based on analysis of intensity profiles along the principal axes of myocytes. The analyses characterized gap junction polarization at cell ends and higher-order statistical image moments of intensity profiles. The methodology was tested in rat ventricular myocardium. Our analysis yielded novel quantitative data on gap junction distributions. In particular, the analysis demonstrated that the distributions exhibit significant variability with respect to polarization, skewness, and kurtosis. We suggest that this methodology provides a quantitative alternative to current approaches based on visual inspection, with applications in particular in characterization of engineered and diseased myocardium. Furthermore, we propose that these data provide improved input for computational modeling of cardiac conduction.

Comparative plasma and tissue distribution of Sun Pharma's generic doxorubicin HCl liposome injection versus Caelyx® (doxorubicin HCl liposome injection) in syngeneic fibrosarcoma-bearing BALB/c mice and Sprague-Dawley rats.

PubMed

Burade, Vinod; Bhowmick, Subhas; Maiti, Kuntal; Zalawadia, Rishit; Jain, Deepak; Rajamannar, Thennati

2017-05-01

The liposomal formulation of doxorubicin [doxorubicin (DXR) hydrochloride (HCl) liposome injection, Caelyx ® ] alters the tissue distribution of DXR as compared with nonliposomal DXR, resulting in an improved benefit-risk profile. We conducted studies in murine models to compare the plasma and tissue distribution of a proposed generic DXR HCl liposome injection developed by Sun Pharmaceuticals Industries Limited (SPIL DXR HCl liposome injection) with Caelyx ® . The plasma and tissue distributions of the SPIL and reference DXR HCl liposome injections were compared in syngeneic fibrosarcoma-bearing BALB/c mice and Sprague-Dawley rats. Different batches and different lots of the same batch of the reference product were also compared with each other. The SPIL and reference DXR HCl liposome injections exhibited generally comparable plasma and tissue distribution profiles in both models. While minor differences were observed between the two products in some tissues, different batches and lots of the reference product also showed some differences in the distribution of various analytes in some tissues. The ratios of estimated free to encapsulated DXR for plasma and tissue were generally comparable between the SPIL and reference DXR HCl liposome injections in both models, indicating similar extents of absorption into the tissues and similar rates of drug release from liposomes. The plasma and tissue distribution profiles of the SPIL and reference DXR HCl liposome injections were shown to be generally comparable. Inconsistencies between the products observed in some tissues were thought to be due to biological variation.

Physiologically Distributed Loading Patterns Drive the Formation of Zonally Organized Collagen Structures in Tissue-Engineered Meniscus.

PubMed

Puetzer, Jennifer L; Bonassar, Lawrence J

2016-07-01

The meniscus is a dense fibrocartilage tissue that withstands the complex loads of the knee via a unique organization of collagen fibers. Attempts to condition engineered menisci with compression or tensile loading alone have failed to reproduce complex structure on the microscale or anatomic scale. Here we show that axial loading of anatomically shaped tissue-engineered meniscus constructs produced spatial distributions of local strain similar to those seen in the meniscus when the knee is loaded at full extension. Such loading drove formation of tissue with large organized collagen fibers, levels of mechanical anisotropy, and compressive moduli that match native tissue. Loading accelerated the development of native-sized and aligned circumferential and radial collagen fibers. These loading patterns contained both tensile and compressive components that enhanced the major biochemical and functional properties of the meniscus, with loading significantly improved glycosaminoglycan (GAG) accumulation 200-250%, collagen accumulation 40-55%, equilibrium modulus 1000-1800%, and tensile moduli 500-1200% (radial and circumferential). Furthermore, this study demonstrates local changes in mechanical environment drive heterogeneous tissue development and organization within individual constructs, highlighting the importance of recapitulating native loading environments. Loaded menisci developed cartilage-like tissue with rounded cells, a dense collagen matrix, and increased GAG accumulation in the more compressively loaded horns, and fibrous collagen-rich tissue in the more tensile loaded outer 2/3, similar to native menisci. Loaded constructs reached a level of organization not seen in any previous engineered menisci and demonstrate great promise as meniscal replacements.

Clean image synthesis and target numerical marching for optical imaging with backscattering light

PubMed Central

Pu, Yang; Wang, Wubao

2011-01-01

Scanning backscattering imaging and independent component analysis (ICA) are used to probe targets hidden in the subsurface of a turbid medium. A new correction procedure is proposed and used to synthesize a “clean” image of a homogeneous host medium numerically from a set of raster-scanned “dirty” backscattering images of the medium with embedded targets. The independent intensity distributions on the surface of the medium corresponding to individual targets are then unmixed using ICA of the difference between the set of dirty images and the clean image. The target positions are localized by a novel analytical method, which marches the target to the surface of the turbid medium until a match with the retrieved independent component is accomplished. The unknown surface property of the turbid medium is automatically accounted for by this method. Employing clean image synthesis and target numerical marching, three-dimensional (3D) localization of objects embedded inside a turbid medium using independent component analysis in a backscattering geometry is demonstrated for the first time, using as an example, imaging a small piece of cancerous prostate tissue embedded in a host consisting of normal prostate tissue. PMID:21483608

LXR activation by GW3965 alters fat tissue distribution and adipose tissue inflammation in ob/ob female mice[S

PubMed Central

Archer, Amena; Stolarczyk, Émilie; Doria, Maria Luisa; Helguero, Luisa; Domingues, Rosário; Howard, Jane K.; Mode, Agneta; Korach-André, Marion; Gustafsson, Jan-Åke

2013-01-01

To investigate the role of liver X receptor (LXR) in adipose tissue metabolism during obesity, ob/ob mice were treated for 5 weeks with the synthetic LXR agonist GW3965. MRI analysis revealed that pharmacological activation of LXR modified fat distribution by decreasing visceral (VS) fat and inversely increasing subcutaneous (SC) fat storage without affecting whole body fat content. This was concordant with opposite regulation by GW3965 of the lipolytic markers hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) in the two fat depots; moreover, the expression of genes involved in lipogenesis was significantly induced in SC fat. Lipidomic analysis suggested that changes in lipid composition in response to GW3965 also varied between VS and SC fat. In both depots, the observed alteration in lipid composition indicated an overall change toward less lipotoxic lipids. Flow cytometry analysis showed decreased immune cell infiltration in adipose tissue of ob/ob mice in response to GW3965 treatment, which in VS fat mainly affected the macrophage population and in SC fat the lymphocyte population. In line with this, the expression and secretion of proinflammatory markers was decreased in both fat deposits with GW3965 treatment. PMID:23446231

A Tissue-Mimicking Ultrasound Test Object Using Droplet Vaporization to Create Point Targets

PubMed Central

Carneal, Catherine M.; Kripfgans, Oliver D.; Krücker, Jochen; Carson, Paul L.; Fowlkes, J. Brian

2012-01-01

Ultrasound test objects containing reference point targets could be useful for evaluating ultrasound systems and phase aberration correction methods. Polyacrylamide gels containing albumin-stabilized droplets (3.6 µm mean diameter) of dodecafluoropentane (DDFP) are being developed for this purpose. Perturbation by ultrasound causes spontaneous vaporization of the superheated droplets to form gas bubbles, a process termed acoustic droplet vaporization (ADV). The resulting bubbles (20 to 160 µm diameter) are small compared with acoustic wavelengths in diagnostic ultrasound and are theoretically suitable for use as point targets (phase errors <20° for typical f-numbers). Bubbles distributed throughout the material are convenient for determining the point spread function in an imaging plane or volume. Cooling the gel causes condensation of the DDFP droplets, which may be useful for storage. Studying ADV in such viscoelastic media could provide insight into potential bioeffects from rapid bubble formation. PMID:21937339

Tissue phosphoproteomics with PolyMAC identifies potential therapeutic targets in a transgenic mouse model of HER2 positive breast cancer

PubMed Central

Searleman, Adam C.; Iliuk, Anton B.; Collier, Timothy S.; Chodosh, Lewis A.; Tao, W. Andy; Bose, Ron

2014-01-01

Altered protein phosphorylation is a feature of many human cancers that can be targeted therapeutically. Phosphopeptide enrichment is a critical step for maximizing the depth of phosphoproteome coverage by MS, but remains challenging for tissue specimens because of their high complexity. We describe the first analysis of a tissue phosphoproteome using polymer-based metal ion affinity capture (PolyMAC), a nanopolymer that has excellent yield and specificity for phosphopeptide enrichment, on a transgenic mouse model of HER2-driven breast cancer. By combining phosphotyrosine immunoprecipitation with PolyMAC, 411 unique peptides with 139 phosphotyrosine, 45 phosphoserine, and 29 phosphothreonine sites were identified from five LC-MS/MS runs. Combining reverse phase liquid chromatography fractionation at pH 8.0 with PolyMAC identified 1571 unique peptides with 1279 phosphoserine, 213 phosphothreonine, and 21 phosphotyrosine sites from eight LC-MS/MS runs. Linear motif analysis indicated that many of the phosphosites correspond to well-known phosphorylation motifs. Analysis of the tyrosine phosphoproteome with the Drug Gene Interaction database uncovered a network of potential therapeutic targets centered on Src family kinases with inhibitors that are either FDA-approved or in clinical development. These results demonstrate that PolyMAC is well suited for phosphoproteomic analysis of tissue specimens. PMID:24723360

A Numerical Investigation of the Electric and Thermal Cell Kill Distributions in Electroporation-Based Therapies in Tissue

PubMed Central

Garcia, Paulo A.; Davalos, Rafael V.; Miklavcic, Damijan

2014-01-01

Electroporation-based therapies are powerful biotechnological tools for enhancing the delivery of exogeneous agents or killing tissue with pulsed electric fields (PEFs). Electrochemotherapy (ECT) and gene therapy based on gene electrotransfer (EGT) both use reversible electroporation to deliver chemotherapeutics or plasmid DNA into cells, respectively. In both ECT and EGT, the goal is to permeabilize the cell membrane while maintaining high cell viability in order to facilitate drug or gene transport into the cell cytoplasm and induce a therapeutic response. Irreversible electroporation (IRE) results in cell kill due to exposure to PEFs without drugs and is under clinical evaluation for treating otherwise unresectable tumors. These PEF therapies rely mainly on the electric field distributions and do not require changes in tissue temperature for their effectiveness. However, in immediate vicinity of the electrodes the treatment may results in cell kill due to thermal damage because of the inhomogeneous electric field distribution and high current density during the electroporation-based therapies. Therefore, the main objective of this numerical study is to evaluate the influence of pulse number and electrical conductivity in the predicted cell kill zone due to irreversible electroporation and thermal damage. Specifically, we simulated a typical IRE protocol that employs ninety 100-µs PEFs. Our results confirm that it is possible to achieve predominant cell kill due to electroporation if the PEF parameters are chosen carefully. However, if either the pulse number and/or the tissue conductivity are too high, there is also potential to achieve cell kill due to thermal damage in the immediate vicinity of the electrodes. Therefore, it is critical for physicians to be mindful of placement of electrodes with respect to critical tissue structures and treatment parameters in order to maintain the non-thermal benefits of electroporation and prevent unnecessary damage to

Label Distribution in Tissues of Wheat Seedlings Cultivated with Tritium-Labeled Leonardite Humic Acid

PubMed Central

Kulikova, Natalia A.; Abroskin, Dmitry P.; Badun, Gennady A.; Chernysheva, Maria G.; Korobkov, Viktor I.; Beer, Anton S.; Tsvetkova, Eugenia A.; Senik, Svetlana V.; Klein, Olga I.; Perminova, Irina V.

2016-01-01

Humic substances (HS) play important roles in the biotic-abiotic interactions of the root plant and soil contributing to plant adaptation to external environments. However, their mode of action on plants remains largely unknown. In this study the HS distribution in tissues of wheat seedlings was examined using tritium-labeled humic acid (HA) derived from leonardite (a variety of lignites) and microautoradiography (MAR). Preferential accumulation of labeled products from tritiated HA was found in the roots as compared to the shoots, and endodermis was shown to be the major control point for radial transport of label into vascular system of plant. Tritium was also found in the stele and xylem tissues indicating that labeled products from tritiated HA could be transported to shoot tissues via the transpiration stream. Treatment with HA lead to an increase in the content of polar lipids of photosynthetic membranes. The observed accumulation of labeled HA products in root endodermis and positive impact on lipid synthesis are consistent with prior reported observations on physiological effects of HS on plants such as enhanced growth and development of lateral roots and improvement/repairs of the photosynthetic status of plants under stress conditions. PMID:27350412

Tissue Distribution and Elimination of Ciguatoxins in Tridacna maxima (Tridacnidae, Bivalvia) Fed Gambierdiscus polynesiensis.

PubMed

Roué, Mélanie; Darius, Hélène Taiana; Ung, André; Viallon, Jérôme; Sibat, Manoella; Hess, Philipp; Amzil, Zouher; Chinain, Mireille

2018-05-10

Ciguatera is a foodborne disease caused by the consumption of seafood contaminated with ciguatoxins (CTXs). Ciguatera-like poisoning events involving giant clams ( Tridacna maxima ) are reported occasionally from Pacific islands communities. The present study aimed at providing insights into CTXs tissue distribution and detoxification rate in giant clams exposed to toxic cells of Gambierdiscus polynesiensis , in the framework of seafood safety assessment. In a first experiment, three groups of tissue (viscera, flesh and mantle) were dissected from exposed individuals, and analyzed for their toxicity using the neuroblastoma cell-based assay (CBA-N2a) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses. The viscera, flesh, and mantle were shown to retain 65%, 25%, and 10% of the total toxin burden, respectively. All tissues reached levels above the safety limit recommended for human consumption, suggesting that evisceration alone, a practice widely used among local populations, is not enough to ensure seafood safety. In a second experiment, the toxin content in contaminated giant clams was followed at different time points (0, 2, 4, and 6 days post-exposure). Observations suggest that no toxin elimination is visible in T. maxima throughout 6 days of detoxification.

Label Distribution in Tissues of Wheat Seedlings Cultivated with Tritium-Labeled Leonardite Humic Acid

NASA Astrophysics Data System (ADS)

Kulikova, Natalia A.; Abroskin, Dmitry P.; Badun, Gennady A.; Chernysheva, Maria G.; Korobkov, Viktor I.; Beer, Anton S.; Tsvetkova, Eugenia A.; Senik, Svetlana V.; Klein, Olga I.; Perminova, Irina V.

2016-06-01

Humic substances (HS) play important roles in the biotic-abiotic interactions of the root plant and soil contributing to plant adaptation to external environments. However, their mode of action on plants remains largely unknown. In this study the HS distribution in tissues of wheat seedlings was examined using tritium-labeled humic acid (HA) derived from leonardite (a variety of lignites) and microautoradiography (MAR). Preferential accumulation of labeled products from tritiated HA was found in the roots as compared to the shoots, and endodermis was shown to be the major control point for radial transport of label into vascular system of plant. Tritium was also found in the stele and xylem tissues indicating that labeled products from tritiated HA could be transported to shoot tissues via the transpiration stream. Treatment with HA lead to an increase in the content of polar lipids of photosynthetic membranes. The observed accumulation of labeled HA products in root endodermis and positive impact on lipid synthesis are consistent with prior reported observations on physiological effects of HS on plants such as enhanced growth and development of lateral roots and improvement/repairs of the photosynthetic status of plants under stress conditions.

Tissue mimicking simulations for temporal enhanced ultrasound-based tissue typing

NASA Astrophysics Data System (ADS)

Bayat, Sharareh; Imani, Farhad; Gerardo, Carlos D.; Nir, Guy; Azizi, Shekoofeh; Yan, Pingkun; Tahmasebi, Amir; Wilson, Storey; Iczkowski, Kenneth A.; Lucia, M. Scott; Goldenberg, Larry; Salcudean, Septimiu E.; Mousavi, Parvin; Abolmaesumi, Purang

2017-03-01

Temporal enhanced ultrasound (TeUS) is an imaging approach where a sequence of temporal ultrasound data is acquired and analyzed for tissue typing. Previously, in a series of in vivo and ex vivo studies we have demonstrated that, this approach is effective for detecting prostate and breast cancers. Evidences derived from our experiments suggest that both ultrasound-signal related factors such as induced heat and tissue-related factors such as the distribution and micro-vibration of scatterers lead to tissue typing information in TeUS. In this work, we simulate mechanical micro-vibrations of scatterers in tissue-mimicking phantoms that have various scatterer densities reflecting benign and cancerous tissue structures. Finite element modeling (FEM) is used for this purpose where the vertexes are scatterers representing cell nuclei. The initial positions of scatterers are determined by the distribution of nuclei segmented from actual digital histology scans of prostate cancer patients. Subsequently, we generate ultrasound images of the simulated tissue structure using the Field II package resulting in a temporal enhanced ultrasound. We demonstrate that the micro-vibrations of scatterers are captured by temporal ultrasound data and this information can be exploited for tissue typing.

A physics-based solver to optimize the illumination of cylindrical targets in spherically distributed high power laser systems.

PubMed

Gourdain, P-A

2017-05-01

In recent years, our understanding of high energy density plasmas has played an important role in improving inertial fusion confinement and in emerging new fields of physics, such as laboratory astrophysics. Every new idea required developing innovative experimental platforms at high power laser facilities, such as OMEGA or NIF. These facilities, designed to focus all their beams onto spherical targets or hohlraum windows, are now required to shine them on more complex targets. While the pointing on planar geometries is relatively straightforward, it becomes problematic for cylindrical targets or target with more complex geometries. This publication describes how the distribution of laser beams on a cylindrical target can be done simply by using a set of physical laws as a pointing procedure. The advantage of the method is threefold. First, it is straightforward, requiring no mathematical enterprise besides solving ordinary differential equations. Second, it will converge if a local optimum exists. Finally, it is computationally inexpensive. Experimental results show that this approach produces a geometrical beam distribution that yields cylindrically symmetric implosions.

A physics-based solver to optimize the illumination of cylindrical targets in spherically distributed high power laser systems

NASA Astrophysics Data System (ADS)

Gourdain, P.-A.

2017-05-01

In recent years, our understanding of high energy density plasmas has played an important role in improving inertial fusion confinement and in emerging new fields of physics, such as laboratory astrophysics. Every new idea required developing innovative experimental platforms at high power laser facilities, such as OMEGA or NIF. These facilities, designed to focus all their beams onto spherical targets or hohlraum windows, are now required to shine them on more complex targets. While the pointing on planar geometries is relatively straightforward, it becomes problematic for cylindrical targets or target with more complex geometries. This publication describes how the distribution of laser beams on a cylindrical target can be done simply by using a set of physical laws as a pointing procedure. The advantage of the method is threefold. First, it is straightforward, requiring no mathematical enterprise besides solving ordinary differential equations. Second, it will converge if a local optimum exists. Finally, it is computationally inexpensive. Experimental results show that this approach produces a geometrical beam distribution that yields cylindrically symmetric implosions.

Laser-induced disruption of systemically administered liposomes for targeted drug delivery

NASA Astrophysics Data System (ADS)

Mackanos, Mark A.; Larabi, Malika; Shinde, Rajesh; Simanovskii, Dmitrii M.; Guccione, Samira; Contag, Christopher H.

2009-07-01

Liposomal formulations of drugs have been shown to enhance drug efficacy by prolonging circulation time, increasing local concentration and reducing off-target effects. Controlled release from these formulations would increase their utility, and hyperthermia has been explored as a stimulus for targeted delivery of encapsulated drugs. Use of lasers as a thermal source could provide improved control over the release of the drug from the liposomes with minimal collateral tissue damage. Appropriate methods for assessing local release after systemic delivery would aid in testing and development of better formulations. We use in vivo bioluminescence imaging to investigate the spatiotemporal distribution of luciferin, used as a model small molecule, and demonstrate laser-induced release from liposomes in animal models after systemic delivery. These liposomes were tested for luciferin release between 37 and 45 °C in PBS and serum using bioluminescence measurements. In vivo studies were performed on transgenic reporter mice that express luciferase constitutively throughout the body, thus providing a noninvasive readout for controlled release following systemic delivery. An Nd:YLF laser was used (527 nm) to heat tissues and induce rupture of the intravenously delivered liposomes in target tissues. These data demonstrate laser-mediated control of small molecule delivery using thermally sensitive liposomal formulations.

Biological tissue component evaluation by measuring photoacoustic spectrum

NASA Astrophysics Data System (ADS)

Namita, Takeshi; Murata, Yuya; Tokuyama, Junji; Kondo, Kengo; Yamakawa, Makoto; Shiina, Tsuyoshi

2017-03-01

Photoacoustic imaging has garnered constant attention as a non-invasive modality for visualizing details of the neovascularization structure of tumors, or the distribution of oxygen saturation, which is related to the tumor grade. However, photoacoustic imaging is applicable not only for vascular imaging but also for diagnosing properties of various tissues such as skin or muscle diseases, fat related to arteriosclerosis or fatty liver, cartilage related to arthritis, and fibrous tissues related to hepatitis. The photoacoustic signal intensity is wavelength-dependent and proportional to the absorption coefficient and thermal acoustic conversion efficiency (i.e. Grüneisen parameter) of the target biological tissue. To ascertain the appropriate wavelength range for biological tissue imaging and to evaluate tissue properties, photoacoustic spectra of various tissues (e.g., skin, muscle, and adipose tissue) were measured using a hydrophone (9 mm diameter) at 680-1600 nm wavelengths. Results confirmed that respective tissues have unique photoacoustic spectra. However, almost all samples have peaks around 1200 nm and 1400-1500 nm for wavelengths where the light absorbance of lipid or water is high. The main components of biological tissues are water, protein, and lipid. Results confirmed that photoacoustic spectra reflect the tissue components well. To evaluate the feasibility of the tissue characterization using photoacoustic methods, the photoacoustic signal intensity ratio between two wavelength regions was calculated as described above. Signal intensity ratios agreed well with the composition ratio between water and lipid in samples. These analyses verified the feasibility of evaluating tissue properties using photoacoustic methods.

Plexin D1 determines body fat distribution by regulating the type V collagen microenvironment in visceral adipose tissue.

PubMed

Minchin, James E N; Dahlman, Ingrid; Harvey, Christopher J; Mejhert, Niklas; Singh, Manvendra K; Epstein, Jonathan A; Arner, Peter; Torres-Vázquez, Jesús; Rawls, John F

2015-04-07

Genome-wide association studies have implicated PLEXIN D1 (PLXND1) in body fat distribution and type 2 diabetes. However, a role for PLXND1 in regional adiposity and insulin resistance is unknown. Here we use in vivo imaging and genetic analysis in zebrafish to show that Plxnd1 regulates body fat distribution and insulin sensitivity. Plxnd1 deficiency in zebrafish induced hyperplastic morphology in visceral adipose tissue (VAT) and reduced lipid storage. In contrast, subcutaneous adipose tissue (SAT) growth and morphology were unaffected, resulting in altered body fat distribution and a reduced VAT:SAT ratio in zebrafish. A VAT-specific role for Plxnd1 appeared conserved in humans, as PLXND1 mRNA was positively associated with hypertrophic morphology in VAT, but not SAT. In zebrafish plxnd1 mutants, the effect on VAT morphology and body fat distribution was dependent on induction of the extracellular matrix protein collagen type V alpha 1 (col5a1). Furthermore, after high-fat feeding, zebrafish plxnd1 mutant VAT was resistant to expansion, and excess lipid was disproportionately deposited in SAT, leading to an even greater exacerbation of altered body fat distribution. Plxnd1-deficient zebrafish were protected from high-fat-diet-induced insulin resistance, and human VAT PLXND1 mRNA was positively associated with type 2 diabetes, suggesting a conserved role for PLXND1 in insulin sensitivity. Together, our findings identify Plxnd1 as a novel regulator of VAT growth, body fat distribution, and insulin sensitivity in both zebrafish and humans.

Advances in oral nano-delivery systems for colon targeted drug delivery in inflammatory bowel disease: selective targeting to diseased versus healthy tissue.

PubMed

Hua, Susan; Marks, Ellen; Schneider, Jennifer J; Keely, Simon

2015-07-01

Colon targeted drug delivery is an active area of research for local diseases affecting the colon, as it improves the efficacy of therapeutics and enables localized treatment, which reduces systemic toxicity. Targeted delivery of therapeutics to the colon is particularly advantageous for the treatment of inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease. Advances in oral drug delivery design have significantly improved the bioavailability of drugs to the colon; however in order for a drug to have therapeutic efficacy during disease, considerations must be made for the altered physiology of the gastrointestinal (GI) tract that is associated with GI inflammation. Nanotechnology has been used in oral dosage formulation design as strategies to further enhance uptake into diseased tissue within the colon. This review will describe some of the physiological challenges faced by orally administered delivery systems in IBD, the important developments in orally administered nano-delivery systems for colon targeting, and the future advances of this research. Inflammatory Bowel Disease (IBD) poses a significant problem for a large number of patients worldwide. Current medical therapy mostly aims at suppressing the active inflammatory episodes. In this review article, the authors described and discussed the various approaches current nano-delivery systems can offer in overcoming the limitations of conventional drug formulations. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Targeted delivery of antigen to hamster nasal lymphoid tissue with M-cell-directed lectins.

PubMed Central

Giannasca, P J; Boden, J A; Monath, T P

1997-01-01

The nasal cavity of a rodent is lined by an epithelium organized into distinct regional domains responsible for specific physiological functions. Aggregates of nasal lymphoid tissue (NALT) located at the base of the nasal cavity are believed to be sites of induction of mucosal immune responses to airborne antigens. The epithelium overlying NALT contains M cells which are specialized for the transcytosis of immunogens, as demonstrated in other mucosal tissues. We hypothesized that NALT M cells are characterized by distinct glycoconjugate receptors which influence antigen uptake and immune responses to transcytosed antigens. To identify glycoconjugates that may distinguish NALT M cells from other cells of the respiratory epithelium (RE), we performed lectin histochemistry on sections of the hamster nasal cavity with a panel of lectins. Many classes of glycoconjugates were found on epithelial cells in this region. While most lectins bound to sites on both the RE and M cells, probes capable of recognizing alpha-linked galactose were found to label the follicle-associated epithelium (FAE) almost exclusively. By morphological criteria, the FAE contains >90% M cells. To determine if apical glycoconjugates on M cells were accessible from the nasal cavity, an M-cell-selective lectin and a control lectin in parallel were administered intranasally to hamsters. The M-cell-selective lectin was found to specifically target the FAE, while the control lectin did not. Lectin bound to M cells in vivo was efficiently endocytosed, consistent with the role of M cells in antigen transport. Intranasal immunization with lectin-test antigen conjugates without adjuvant stimulated induction of specific serum immunoglobulin G, whereas antigen alone or admixed with lectin did not. The selective recognition of NALT M cells by a lectin in vivo provides a model for microbial adhesin-host cell receptor interactions on M cells and the targeted delivery of immunogens to NALT following intranasal

Viral load, tissue distribution and histopathological lesions in goats naturally and experimentally infected with the Small Ruminant Lentivirus Genotype E (subtype E1 Roccaverano strain).

PubMed

Grego, E; Reina, R; Lanfredini, S; Tursi, M; Favole, A; Profiti, M; Lungu, M M; Perona, G; Gay, L; Stella, M C; DeMeneghi, D

2018-06-01

Small Ruminant Lentivirus (SRLV) subtype E1, also known as Roccaverano strain, is considered a low pathogenic virus on the basis of natural genetic deletions, in vitro properties and on-farm observations. In order to gain more knowledge on this atypical lentivirus we investigated the in vivo tropism of Roccaverano strain in both, experimentally and naturally infected goats. Antibody responses were monitored as well as tissue distribution and viral load, evaluated by real time PCR on single spliced (gag/env) and multiple spliced (rev) RNA targets respectively, that were compared to histopathological lesions. Lymph nodes, spleen, alveolar macrophages and mammary gland turned out to be the main tissue reservoirs of genotype E1-provirus. Moreover, mammary gland and/or mammary lymph nodes acted as active replication sites in dairy goats, supporting the lactogenic transmission of this virus. Notably, a direct association between viral load and concomitant infection or inflammatory processes was evident within organs such as spleen, lung and testis. Our results validate the low pathogenicity designation of SRLV genotype E1 in vivo, and confirm the monocyte-macrophage cell lineage as the main virus reservoir of this genotype. Accordingly, SRLV genotype E displays a tropism towards all tissues characterized by an abundant presence of these cells, either for their own anatomical structure or for an occasional infectious/inflammatory status. Copyright © 2018 Elsevier Ltd. All rights reserved.

Full scattering profile of tissues with elliptical cross sections

NASA Astrophysics Data System (ADS)

Duadi, H.; Feder, I.; Fixler, D.

2018-02-01

Light reflectance and transmission from soft tissue has been utilized in noninvasive clinical measurement devices such as the photoplethysmograph (PPG) and reflectance pulse oximeter. Most methods of near infrared (NIR) spectroscopy focus on the volume reflectance from a semi-infinite sample, while very few measure transmission. However, since PPG and pulse oximetry are usually measured on tissue such as earlobe, fingertip, lip and pinched tissue, we propose examining the full scattering profile (FSP), which is the angular distribution of exiting photons. The FSP provides more comprehensive information when measuring from a cylindrical tissue. In our work we discovered a unique point, that we named the iso-pathlength (IPL) point, which is not dependent on changes in the reduced scattering coefficient (µs'). This IPL point was observed both in Monte Carlo (MC) simulation and in experimental tissue mimicking phantoms. The angle corresponding to this IPL point depends only on the tissue geometry. In the case of cylindrical tissues this point linearly depends on the tissue diameter. Since the target tissues for clinically physiological measuring are not a perfect cylinder, in this work we will examine how the change in the tissue cross section geometry influences the FSP and the IPL point. We used a MC simulation to compare a circular to an elliptic tissue cross section. The IPL point can serve as a self-calibration point for optical tissue measurements such as NIR spectroscopy, PPG and pulse oximetery.

Tissue distribution, metabolism and hepatic tissue injury in Chinese lizards (Eremias argus) after a single oral administration of lambda-cyhalothrin.

PubMed

Chang, Jing; Li, Jitong; Wang, Huili; Wang, Yinghuan; Guo, Baoyuan; Yin, Jing; Hao, Weiyu; Li, Wei; Li, Jianzhong; Xu, Peng

2016-11-01

Lambda-cyhalothrin (LCT) is a widely used pyrethroid with neurotoxicity. However, little is known about the toxicokinetics of LCT in reptiles. In this study, the absorption, distribution, metabolism and excretion of LCT in Chinese lizards (Eremias Argus) were determined following a single dose (10 mg kg -1 ) treatment. In the liver, brain, gonads and skin, LCT levels peaked within several hours and then decreased rapidly. However, the concentration of LCT gradually increased in the fat tissue. More than 90% of the LCT dose was excreted in the faeces. One LCT metabolite, 3-phenoxybenzoic acid (PBA), was detected in lizard plasma and tissues. PBA preferentially accumulates in the brain and plasma. The half-life of PBA in the brain was 3.2 days, which was 35.4-fold greater than that of LCT. In the plasma, the concentration of PBA was significantly higher than that of LCT. The bioaccumulation of LCT in tissues was enantioselective, and the enantiomeric fractions (EF) ranged from 0.72 to 0.26. The preferential accumulation of enantiomers changed according to exposure time, but the reasons behind this phenomenon were not clear. For pathological analysis, vacuolation of the cytoplasm and large areas of necrosis were observed in the liver sections after 168 h of dosing. The liver tissues exhibited both decreases in the hepatosomatic index and histopathological lesions during the exposure period. In this study, the effect concentration of LCT in lizards was 200-fold lower than its LD 50 value used in risk assessments for birds. These results may provide additional information for the risk assessment of LCT for reptiles and indicate that birds may not be an ideal surrogate for reptile toxicity evaluation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Multi-source feature extraction and target recognition in wireless sensor networks based on adaptive distributed wavelet compression algorithms

NASA Astrophysics Data System (ADS)

Hortos, William S.

2008-04-01

Proposed distributed wavelet-based algorithms are a means to compress sensor data received at the nodes forming a wireless sensor network (WSN) by exchanging information between neighboring sensor nodes. Local collaboration among nodes compacts the measurements, yielding a reduced fused set with equivalent information at far fewer nodes. Nodes may be equipped with multiple sensor types, each capable of sensing distinct phenomena: thermal, humidity, chemical, voltage, or image signals with low or no frequency content as well as audio, seismic or video signals within defined frequency ranges. Compression of the multi-source data through wavelet-based methods, distributed at active nodes, reduces downstream processing and storage requirements along the paths to sink nodes; it also enables noise suppression and more energy-efficient query routing within the WSN. Targets are first detected by the multiple sensors; then wavelet compression and data fusion are applied to the target returns, followed by feature extraction from the reduced data; feature data are input to target recognition/classification routines; targets are tracked during their sojourns through the area monitored by the WSN. Algorithms to perform these tasks are implemented in a distributed manner, based on a partition of the WSN into clusters of nodes. In this work, a scheme of collaborative processing is applied for hierarchical data aggregation and decorrelation, based on the sensor data itself and any redundant information, enabled by a distributed, in-cluster wavelet transform with lifting that allows multiple levels of resolution. The wavelet-based compression algorithm significantly decreases RF bandwidth and other resource use in target processing tasks. Following wavelet compression, features are extracted. The objective of feature extraction is to maximize the probabilities of correct target classification based on multi-source sensor measurements, while minimizing the resource expenditures at

Effect of surface condition to temperature distribution in living tissue during cryopreservation

NASA Astrophysics Data System (ADS)

Nozawa, M.; Hatakeyama, S.; Sugimoto, Y.; Sasaki, H.

2017-12-01

The temperature distribution of the simulated living tissue is measured for the improvement of the cooling rate during cryopreservation when the surface condition of the test sample is changed by covering the stainless steel mesh. Agar is used as a simulated living tissue and is filled inside the test sample. The variation of the transient temperature with mesh by the directly immersion in the liquid nitrogen is measured. The temperatures on the sample surface and the inside of the sample are measured by use of type T thermocouples. It is confirmed that on the sample surface there is the slightly temperature increase than that in the saturated liquid nitrogen at the atmospheric pressure. It is found by the comparison of the degree of superheat with or without the mesh that the surface temperature of the test sample with the mesh is lower than that without the mesh. On the other hand, the time series variations of the temperature located in the center of the sample does not change with or without the mesh. It is considered that the center of the sample used is too deep from the surface to respond to the boiling state on the sample surface.

Tissue Distribution of the 27.8 kDa Receptor and its Dynamic Expression in Response to Lymphocystis Disease Virus Infection in Flounder (Paralichthys olivaceus).

PubMed

Wu, R-H; Tang, X-Q; Sheng, X-Z; Zhan, W-B

2015-11-01

Lymphocystis disease virus (LCDV) enters and infects the gill cells of flounder (Paralichthys olivaceus) via a 27.8 kDa membrane protein receptor. In the present study, immunohistochemistry was performed to locate the tissue distribution of this molecule in healthy flounder and showed that it was widely distributed in the tissues tested. Indirect enzyme-linked immunosorbent assay (ELISA) showed that the expression of the receptor in healthy flounder was highest in the gills and stomach, then in the skin, intestine and liver, followed by the spleen, head kidney, heart, ovary and brain and finally the kidney. On LCDV infection, ELISA indicated that the expression of the receptor, as determined by ELISA, was significantly upregulated in all tissues of LCDV-infected flounder compared with controls, but this expression decreased over the 4 weeks post infection. In contrast, real-time quantitative polymerase chain reaction demonstrated that the copy number of the LCDV gene in the tissues increased with time post infection, and that viral loads were higher in the tissues with higher expressions of the receptor. These results point to a correlation between high expression of the 27.8 kDa receptor and efficient LCDV propagation. The wide tissue distribution of the receptor might be one reason why LCDV can infect various tissues leading to systemic infection. Copyright © 2015 Elsevier Ltd. All rights reserved.

Artificial Chemical Reporter Targeting Strategy Using Bioorthogonal Click Reaction for Improving Active-Targeting Efficiency of Tumor.

PubMed

Yoon, Hong Yeol; Shin, Min Lee; Shim, Man Kyu; Lee, Sangmin; Na, Jin Hee; Koo, Heebeom; Lee, Hyukjin; Kim, Jong-Ho; Lee, Kuen Yong; Kim, Kwangmeyung; Kwon, Ick Chan

2017-05-01

Biological ligands such as aptamer, antibody, glucose, and peptide have been widely used to bind specific surface molecules or receptors in tumor cells or subcellular structures to improve tumor-targeting efficiency of nanoparticles. However, this active-targeting strategy has limitations for tumor targeting due to inter- and intraheterogeneity of tumors. In this study, we demonstrated an alternative active-targeting strategy using metabolic engineering and bioorthogonal click reaction to improve tumor-targeting efficiency of nanoparticles. We observed that azide-containing chemical reporters were successfully generated onto surface glycans of various tumor cells such as lung cancer (A549), brain cancer (U87), and breast cancer (BT-474, MDA-MB231, MCF-7) via metabolic engineering in vitro. In addition, we compared tumor targeting of artificial azide reporter with bicyclononyne (BCN)-conjugated glycol chitosan nanoparticles (BCN-CNPs) and integrin α v β 3 with cyclic RGD-conjugated CNPs (cRGD-CNPs) in vitro and in vivo. Fluorescence intensity of azide-reporter-targeted BCN-CNPs in tumor tissues was 1.6-fold higher and with a more uniform distribution compared to that of cRGD-CNPs. Moreover, even in the isolated heterogeneous U87 cells, BCN-CNPs could bind artificial azide reporters on tumor cells more uniformly (∼92.9%) compared to cRGD-CNPs. Therefore, the artificial azide-reporter-targeting strategy can be utilized for targeting heterogeneous tumor cells via bioorthogonal click reaction and may provide an alternative method of tumor targeting for further investigation in cancer therapy.

Effect of wine and vinegar processing of Rhizoma Corydalis on the tissue distribution of tetrahydropalmatine, protopine and dehydrocorydaline in rats.

PubMed

Dou, Zhiying; Li, Kefeng; Wang, Ping; Cao, Liu

2012-01-18

Vinegar and wine processing of medicinal plants are two traditional pharmaceutical techniques which have been used for thousands of years in China. Tetrahydropalmatine (THP), dehydrocorydaline (DHC) and protopine are three major bioactive molecules in Rhizoma Corydalis. In this study, a simple and reliable HPLC method was developed for simultaneous analysis of THP, DHC and protopine in rat tissues after gastric gavage administration of Rhizoma Corydalis. The validated HPLC method was successfully applied to investigate the effect of wine and vinegar processing on the compounds' distribution in rat tissues. Our results showed that processing mainly affect the T(max) and mean residence time (MRT) of the molecules without changing their C(max) and AUC(0-24)( )(h) Vinegar processing significantly increased the T(max) of DHC in heart, kidney, cerebrum, cerebrellum, brain stem and striatum and prolonged the T(max) of protopine in brain. No significant changes were observed on the T(max) of THP in rat tissues after vinegar processing. Wine processing reduced the T(max) of protopine and DHC in liver and spleen and T(max) of protopine in lung, but increased the T(max) of THP in all the rat tissues examined. To our knowledge, this is the first report on the effects of processing on the tissue distribution of the bioactive molecules from Rhizoma Corydalis.

A Targeted Quantitative Proteomics Strategy for Global Kinome Profiling of Cancer Cells and Tissues*

PubMed Central

Xiao, Yongsheng; Guo, Lei; Wang, Yinsheng

2014-01-01

Kinases are among the most intensively pursued enzyme superfamilies as targets for anti-cancer drugs. Large data sets on inhibitor potency and selectivity for more than 400 human kinases became available recently, offering the opportunity to design rationally novel kinase-based anti-cancer therapies. However, the expression levels and activities of kinases are highly heterogeneous among different types of cancer and even among different stages of the same cancer. The lack of effective strategy for profiling the global kinome hampers the development of kinase-targeted cancer chemotherapy. Here, we introduced a novel global kinome profiling method, based on our recently developed isotope-coded ATP-affinity probe and a targeted proteomic method using multiple-reaction monitoring (MRM), for assessing simultaneously the expression of more than 300 kinases in human cells and tissues. This MRM-based assay displayed much better sensitivity, reproducibility, and accuracy than the discovery-based shotgun proteomic method. Approximately 250 kinases could be routinely detected in the lysate of a single cell line. Additionally, the incorporation of iRT into MRM kinome library rendered our MRM kinome assay easily transferrable across different instrument platforms and laboratories. We further employed this approach for profiling kinase expression in two melanoma cell lines, which revealed substantial kinome reprogramming during cancer progression and demonstrated an excellent correlation between the anti-proliferative effects of kinase inhibitors and the expression levels of their target kinases. Therefore, this facile and accurate kinome profiling assay, together with the kinome-inhibitor interaction map, could provide invaluable knowledge to predict the effectiveness of kinase inhibitor drugs and offer the opportunity for individualized cancer chemotherapy. PMID:24520089

Bioavailability, Pharmacokinetics and Tissue Distribution of P57AS3 (P57) from Hoodia gordonii Mouse Model

USDA-ARS?s Scientific Manuscript database

P57AS3, an oxypregnane steroidal glycoside (P57) is known to be responsible for the diet suppressing activity of Hoodia gordonii, a dietary supplement used for weight loss. In this study, bioavailability, pharmacokinetics and tissue distribution of P57 was determined in CD1 female mice after adminis...

Pharmacokinetics, bioavailability, tissue distribution and excretion of tangeretin in rat.

PubMed

Hung, Wei-Lun; Chang, Wei-Shan; Lu, Wen-Chien; Wei, Guor-Jien; Wang, Yu; Ho, Chi-Tang; Hwang, Lucy Sun

2018-04-01

Tangeretin, 4',5,6,7,8-pentamethoxyflavone, is one of the major polymethoxyflavones (PMFs) existing in citrus fruits, particularly in the peels of sweet oranges and mandarins. Tangeretin has been reported to possess several beneficial bioactivities including anti-inflammatory, anti-proliferative and neuroprotective effects. To achieve a thorough understanding of the biological actions of tangeretin in vivo, our current study is designed to investigate the pharmacokinetics, bioavailability, distribution and excretion of tangeretin in rats. After oral administration of 50 mg/kg bw tangeretin to rats, the C max , T max and t 1/2 were 0.87 ± 0.33 μg/mL, 340.00 ± 48.99 min and 342.43 ± 71.27 min, respectively. Based on the area under the curves (AUC) of oral and intravenous administration of tangeretin, calculated absolute oral bioavailability was 27.11%. During tissue distribution, maximum concentrations of tangeretin in the vital organs occurred at 4 or 8 h after oral administration. The highest accumulation of tangeretin was found in the kidney, lung and liver, followed by spleen and heart. In the gastrointestinal tract, maximum concentrations of tangeretin in the stomach and small intestine were found at 4 h, while in the cecum, colon and rectum, tangeretin reached the maximum concentrations at 12 h. Tangeretin excreted in the urine and feces was recovered within 48 h after oral administration, concentrations were only 0.0026% and 7.54%, respectively. These results suggest that tangeretin was mainly eliminated as metabolites. In conclusion, our study provides useful information regarding absorption, distribution, as well as excretion of tangeretin, which will provide a good base for studying the mechanism of its biological effects. Copyright © 2017. Published by Elsevier B.V.

A motion algorithm to extract physical and motion parameters of mobile targets from cone-beam computed tomographic images.

PubMed

Alsbou, Nesreen; Ahmad, Salahuddin; Ali, Imad

2016-05-17

A motion algorithm has been developed to extract length, CT number level and motion amplitude of a mobile target from cone-beam CT (CBCT) images. The algorithm uses three measurable parameters: Apparent length and blurred CT number distribution of a mobile target obtained from CBCT images to determine length, CT-number value of the stationary target, and motion amplitude. The predictions of this algorithm are tested with mobile targets having different well-known sizes that are made from tissue-equivalent gel which is inserted into a thorax phantom. The phantom moves sinusoidally in one-direction to simulate respiratory motion using eight amplitudes ranging 0-20 mm. Using this motion algorithm, three unknown parameters are extracted that include: Length of the target, CT number level, speed or motion amplitude for the mobile targets from CBCT images. The motion algorithm solves for the three unknown parameters using measured length, CT number level and gradient for a well-defined mobile target obtained from CBCT images. The motion model agrees with the measured lengths which are dependent on the target length and motion amplitude. The gradient of the CT number distribution of the mobile target is dependent on the stationary CT number level, the target length and motion amplitude. Motion frequency and phase do not affect the elongation and CT number distribution of the mobile target and could not be determined. A motion algorithm has been developed to extract three parameters that include length, CT number level and motion amplitude or speed of mobile targets directly from reconstructed CBCT images without prior knowledge of the stationary target parameters. This algorithm provides alternative to 4D-CBCT without requirement of motion tracking and sorting of the images into different breathing phases. The motion model developed here works well for tumors that have simple shapes, high contrast relative to surrounding tissues and move nearly in regular motion pattern

Influence of nuclear interactions in body tissues on tumor dose in carbon-ion radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Inaniwa, T., E-mail: taku@nirs.go.jp; Kanematsu, N.; Tsuji, H.

2015-12-15

Purpose: In carbon-ion radiotherapy treatment planning, the planar integrated dose (PID) measured in water is applied to the patient dose calculation with density scaling using the stopping power ratio. Since body tissues are chemically different from water, this dose calculation can be subject to errors, particularly due to differences in inelastic nuclear interactions. In recent studies, the authors proposed and validated a PID correction method for these errors. In the present study, the authors used this correction method to assess the influence of these nuclear interactions in body tissues on tumor dose in various clinical cases. Methods: Using 10–20 casesmore » each of prostate, head and neck (HN), bone and soft tissue (BS), lung, liver, pancreas, and uterine neoplasms, the authors first used treatment plans for carbon-ion radiotherapy without nuclear interaction correction to derive uncorrected dose distributions. The authors then compared these distributions with recalculated distributions using the nuclear interaction correction (corrected dose distributions). Results: Median (25%/75% quartiles) differences between the target mean uncorrected doses and corrected doses were 0.2% (0.1%/0.2%), 0.0% (0.0%/0.0%), −0.3% (−0.4%/−0.2%), −0.1% (−0.2%/−0.1%), −0.1% (−0.2%/0.0%), −0.4% (−0.5%/−0.1%), and −0.3% (−0.4%/0.0%) for the prostate, HN, BS, lung, liver, pancreas, and uterine cases, respectively. The largest difference of −1.6% in target mean and −2.5% at maximum were observed in a uterine case. Conclusions: For most clinical cases, dose calculation errors due to the water nonequivalence of the tissues in nuclear interactions would be marginal compared to intrinsic uncertainties in treatment planning, patient setup, beam delivery, and clinical response. In some extreme cases, however, these errors can be substantial. Accordingly, this correction method should be routinely applied to treatment planning in clinical practice.« less

Performance of different theories for the angular distribution of bremsstrahlung produced by keV electrons incident upon a target

NASA Astrophysics Data System (ADS)

Omar, Artur; Andreo, Pedro; Poludniowski, Gavin

2018-07-01

Different theories of the intrinsic bremsstrahlung angular distribution (i.e., the shape function) have been evaluated using Monte Carlo calculations for various target materials and incident electron energies between 20 keV and 300 keV. The shape functions considered were the plane-wave first Born approximation cross sections (i) 2BS [high-energy result, screened nucleus], (ii) 2BN [general result, bare nucleus], (iii) KM [2BS modified to emulate 2BN], and (iv) SIM [leading term of 2BN]; (v) expression based on partial-waves expansion, KQP; and (vi) a uniform spherical distribution, UNI [a common approximation in certain analytical models]. The shape function was found to have an important impact on the bremsstrahlung emerging from thin foil targets in which the incident electrons undergo few elastic scatterings before exiting the target material. For thick transmission and reflection targets the type of shape function had less importance, as the intrinsic bremsstrahlung angular distribution was masked by the diffuse directional distribution of multiple scattered electrons. Predictions made using the 2BN and KQP theories were generally in good agreement, suggesting that the effect of screening and the constraints of the Born approximation on the intrinsic angular distribution may be acceptable. The KM and SIM shape functions deviated notably from KQP for low electron energies (< 50 keV), while 2BS and UNI performed poorly over most of the energy range considered; the 2BS shape function was found to be too forward-focused in emission, while UNI was not forward-focused enough. The results obtained emphasize the importance of the intrinsic bremsstrahlung angular distribution for theoretical predictions of x-ray emission, which is relevant in various applied disciplines, including x-ray crystallography, electron-probe microanalysis, security and industrial inspection, medical imaging, as well as low- and medium (orthovoltage) energy radiotherapy.

Distribution and accumulation of mercury in tissues of captive-reared common loon (Gavia immer) chicks

USGS Publications Warehouse

Kenow, K.P.; Meyer, M.W.; Hines, R.K.; Karasov, W.H.

2007-01-01

We determined the distribution and accumulation of Hg in tissues of common loon (Gavia immer) chicks maintained for up to 15 weeks on either a control diet with no added methylmercury chloride (MeHgCl) or one containing either 0.4 or 1.2 ??g Hg (as MeHgCl)/g wet-weight food. Total Hg and MeHg tissue concentrations were strongly positively correlated (r2 > 0.95) with the amount of Hg delivered to individual chicks throughout the course of the experiment. The pattern of differential Hg concentration in internal tissues was consistent within each treatment: Liver > kidney > muscle > carcass > brain. Feather Hg concentrations were consistently higher than those of internal tissues and represented an important route of Hg elimination. Feather mass accounted for 4.3% ?? 0.1% (average ?? standard error) of body mass, yet 27.3% ?? 2.6% of total Hg intake was excreted into feathers. Our calculations indicate that 26.7% ?? 4.9% of ingested Hg was not accounted for and, thus, either was never absorbed or was absorbed and subsequently eliminated in feces. With the additional excretion into feathers, 54% of ingested Hg was excreted. Demethylation was evident in the liver at all treatment levels and in the kidneys of chicks dosed at 1.2 ??g Hg/g. Mercury concentrations were strongly positively correlated (r2 ??? 0.95) among internal tissues and with blood Hg concentration. Mercury concentrations of secondary feathers were moderately correlated (r2 = 0.82-0.93) with internal tissues. We supply regression models that may be used to provide perspective and a useful means of interpreting the variety of measures of Hg exposure reported in the literature. ?? 2007 SETAC.

Detergent Lysis of Animal Tissues for Immunoprecipitation.

PubMed

DeCaprio, James; Kohl, Thomas O

2017-12-01

This protocol details protein extraction from mouse tissues for immunoprecipitation purposes and has been applied for the performance of large-scale immunoprecipitations of target proteins from various tissues for the identification of associated proteins by mass spectroscopy. The key factors in performing a successful immunoprecipitation directly relate to the abundance of target protein in a particular tissue type and whether or not the embryonic, newborn, or adult mouse-derived tissues contain fibrous and other insoluble material. Several tissue types, including lung and liver as well as carcinomas, contain significant amounts of fibrous tissue that can interfere with an immunoprecipitation. © 2017 Cold Spring Harbor Laboratory Press.

Scaffolds and tissue regeneration: An overview of the functional properties of selected organic tissues.

PubMed

Rebelo, Márcia A; Alves, Thais F R; de Lima, Renata; Oliveira, José M; Vila, Marta M D C; Balcão, Victor M; Severino, Patrícia; Chaud, Marco V

2016-10-01

Tissue engineering plays a significant role both in the re-establishment of functions and regeneration of organic tissues. Success in manufacturing projects for biological scaffolds, for the purpose of tissue regeneration, is conditioned by the selection of parameters such as the biomaterial, the device architecture, and the specificities of the cells making up the organic tissue to create, in vivo, a microenvironment that preserves and further enhances the proliferation of a specific cell phenotype. To support this approach, we have screened scientific publications that show biomedical applications of scaffolds, biomechanical, morphological, biochemical, and hemodynamic characteristics of the target organic tissues, and the possible interactions between different cell matrices and biological scaffolds. This review article provides an overview on the biomedical application of scaffolds and on the characteristics of the (bio)materials commonly used for manufacturing these biological devices used in tissue engineering, taking into consideration the cellular specificity of the target tissue. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1483-1494, 2016. © 2015 Wiley Periodicals, Inc.

Tissue distribution, metabolism and excretion of 3, 3′-dichloro-4′-sulfooxy-biphenyl in the rat

PubMed Central

Grimm, Fabian A.; He, Xianran; Teesch, Lynn M.; Lehmler, Hans-Joachim; Robertson, Larry W.; Duffel, Michael W.

2015-01-01

Polychlorinated biphenyls (PCBs) with lower numbers of chlorine atoms exhibit a greater susceptibility to metabolism than their higher-chlorinated counterparts. Following initial hydroxylation of these lower chlorinated PCBs, metabolic sulfation to form PCB sulfates is increasingly recognized as an important component of their toxicology. Since procedures for the quantitative analysis of PCB sulfates in tissue samples have not been previously available, we have now developed an efficient, LC-ESI-MS/MS based, protocol for the quantitative analysis of 4-PCB 11 sulfate in biological samples. This procedure was used to determine the distribution of 4-PCB 11 sulfate in liver, kidney, lung, and brain, as well as its excretion profile, following its intravenous administration to male Sprague-Dawley rats. Following initial uptake of 4-PCB 11 sulfate, its concentration in these tissues and serum declined within the first hour following injection. Although biliary secretion was detected, analysis of 24 hour collections of urine and feces revealed recovery of less than 4% of the administered 4-PCB 11 sulfate. High-resolution LC-MS analysis of bile, urine, and feces showed metabolic products derived from 4-PCB 11 sulfate. Thus, 4-PCB 11 sulfate at this dose was not directly excreted in the urine, but was, instead, re-distributed to tissues and/or subjected to further metabolism. PMID:26046945

Ewing's Sarcoma: An Analysis of miRNA Expression Profiles and Target Genes in Paraffin-Embedded Primary Tumor Tissue.

PubMed

Parafioriti, Antonina; Bason, Caterina; Armiraglio, Elisabetta; Calciano, Lucia; Daolio, Primo Andrea; Berardocco, Martina; Di Bernardo, Andrea; Colosimo, Alessia; Luksch, Roberto; Berardi, Anna C

2016-04-30

The molecular mechanism responsible for Ewing's Sarcoma (ES) remains largely unknown. MicroRNAs (miRNAs), a class of small non-coding RNAs able to regulate gene expression, are deregulated in tumors and may serve as a tool for diagnosis and prediction. However, the status of miRNAs in ES has not yet been thoroughly investigated. This study compared global miRNAs expression in paraffin-embedded tumor tissue samples from 20 ES patients, affected by primary untreated tumors, with miRNAs expressed in normal human mesenchymal stromal cells (MSCs) by microarray analysis. A miRTarBase database was used to identify the predicted target genes for differentially expressed miRNAs. The miRNAs microarray analysis revealed distinct patterns of miRNAs expression between ES samples and normal MSCs. 58 of the 954 analyzed miRNAs were significantly differentially expressed in ES samples compared to MSCs. Moreover, the qRT-PCR analysis carried out on three selected miRNAs showed that miR-181b, miR-1915 and miR-1275 were significantly aberrantly regulated, confirming the microarray results. Bio-database analysis identified BCL-2 as a bona fide target gene of the miR-21, miR-181a, miR-181b, miR-29a, miR-29b, miR-497, miR-195, miR-let-7a, miR-34a and miR-1915. Using paraffin-embedded tissues from ES patients, this study has identified several potential target miRNAs and one gene that might be considered a novel critical biomarker for ES pathogenesis.

A study of a tissue equivalent gelatine based tissue substitute

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spence, J.L.

1992-11-01

A study of several tissue substitutes for use as volumetric dosimeters was performed. The tissue substitutes studied included tissue substitutes from previous studies and from ICRU 44. The substitutes were evaluated for an overall match to Reference Man which was used as a basis for this study. The evaluation was based on the electron stopping power, the mass attenuation coefficient, the electron density, and the specific gravity. The tissue substitute chosen also had to be capable of changing from a liquid into a solid form to maintain an even distribution of thermoluminesent dosimetry (TLD) powder and then back to amore » liquid for recovery of the TLD powder without adversely effecting the TLD powder. The gelatine mixture provided the closest match to the data from Reference Man tissue. The gelatine mixture was put through a series of test to determine it's usefulness as a reliable tissue substitute. The TLD powder was cast in the gelatine mixture and recovered to determine if the TLD powder was adversely effected. The distribution of the TLD powder after being cast into the gelatin mixture was tested in insure an even was maintained.« less

A study of a tissue equivalent gelatine based tissue substitute

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spence, Jody L.

1992-11-01

A study of several tissue substitutes for use as volumetric dosimeters was performed. The tissue substitutes studied included tissue substitutes from previous studies and from ICRU 44. The substitutes were evaluated for an overall match to Reference Man which was used as a basis for this study. The evaluation was based on the electron stopping power, the mass attenuation coefficient, the electron density, and the specific gravity. The tissue substitute chosen also had to be capable of changing from a liquid into a solid form to maintain an even distribution of thermoluminesent dosimetry (TLD) powder and then back to amore » liquid for recovery of the TLD powder without adversely effecting the TLD powder. The gelatine mixture provided the closest match to the data from Reference Man tissue. The gelatine mixture was put through a series of test to determine it`s usefulness as a reliable tissue substitute. The TLD powder was cast in the gelatine mixture and recovered to determine if the TLD powder was adversely effected. The distribution of the TLD powder after being cast into the gelatin mixture was tested in insure an even was maintained.« less

Post heroin dose tissue distribution of 6-monoacetylmorphine (6-MAM) with MALDI imaging.

PubMed

Teklezgi, Belin G; Pamreddy, Annapurna; Baijnath, Sooraj; Gopal, Nirmala D; Naicker, Tricia; Kruger, Hendrik G; Govender, Thavendran

2017-08-01

Heroin is an illicit opioid drug which is commonly abused and leads to dependence and addiction. Heroin is considered a pro-drug and is rapidly converted to its major active metabolite 6-monoacetylmorphine (6-MAM) which mediates euphoria and reward through the stimulation of opioid receptors in the brain. The aim of this study was to investigate the distribution and localization of 6-MAM in the healthy Sprague Dawley rat brain following intraperitoneal (i.p) administration of heroin (10 mg/kg), using matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI), in combination with quantification via liquid chromatography mass spectrometry (LC-MS/MS). These findings revealed that 6-MAM is present both in plasma and brain tissue with a T max of 5 min (2.8 µg/mL) and 15 min (1.1 µg/mL), respectively. MSI analysis of the brain showed high intensities of 6-MAM in the thalamus-hypothalamus and mesocorticolimbic system including areas of the cortex, caudate putamen, and ventral pallidum regions. This finding correlates with the distribution of opioid receptors in the brain, according to literature. In addition, we report a time-dependent distribution in the levels of 6-MAM, from 1 min with the highest intensity of the drug observed at 15 min, with sparse distribution at 45 min before decreasing at 60 min. This is the first study to use MSI as a brain imaging technique to detect a morphine's distribution over time in the brain.

Injectable 3-D Fabrication of Medical Electronics at the Target Biological Tissues

NASA Astrophysics Data System (ADS)

Jin, Chao; Zhang, Jie; Li, Xiaokang; Yang, Xueyao; Li, Jingjing; Liu, Jing

2013-12-01

Conventional transplantable biomedical devices generally request sophisticated surgery which however often causes big trauma and serious pain to the patients. Here, we show an alternative way of directly making three-dimensional (3-D) medical electronics inside the biological body through sequential injections of biocompatible packaging material and liquid metal ink. As the most typical electronics, a variety of medical electrodes with different embedded structures were demonstrated to be easily formed at the target tissues. Conceptual in vitro experiments provide strong evidences for the excellent performances of the injectable electrodes. Further in vivo animal experiments disclosed that the formed electrode could serve as both highly efficient ECG (Electrocardiograph) electrode and stimulator electrode. These findings clarified the unique features and practicability of the liquid metal based injectable 3-D fabrication of medical electronics. The present strategy opens the way for directly manufacturing electrophysiological sensors or therapeutic devices in situ via a truly minimally invasive approach.

Tissue distribution and lipophorin transport of hydrocarbons and sex pheromones in the house fly, Musca domestica

PubMed Central

Schal, Coby; Sevala, Veeresh; de L.Capurro, Margareth; Snyder, Theodore E.; Blomquist, Gary J.; Bagnères, Anne–Geneviève

2001-01-01

We investigated the relationship between epicuticular and internal hydrocarbons in the adult house fly, Musca domestica and the distribution of hydrocarbons, including the female sex pheromone component, (Z)-9-tricosene, in tissues. Internal hydrocarbons increased dramatically in relation to sexual maturation and were found in the hemolymph, ovaries, digestive tract, and fat body. (Z)-9-Tricosene comprised a relatively large fraction of the hydrocarbons in the female carcass and hemolymph, and less so in other tissues, while other hydrocarbons were represented in greater amounts in the ovaries than in other tissues. It therefore appears that certain hydrocarbons were selectively provisioned to certain tissues such as the ovaries, from which pheromone was relatively excluded. Both KBr gradient ultracentrifugation and specific immunoprecipitation indicated that > 90% of hemolymph hydrocarbons were associated with a high-density lipophorin (density = 1.09 g ml−1), composed of two apoproteins under denaturing conditions, apolipophorin I (∼240 kD) and apolipophorin II (∼85 kD). Our results support a predicted model (Chino, 1985) that lipophorin is involved in the transport of sex pheromone in M. domestica. In addition to delivering hydrocarbons and sex pheromones to the cuticular surface, we suggest that lipophorin may play an important role in an active mechanism that selectively deposits certain subsets of hydrocarbons at specific tissues. PMID:15455072

Tissue distribution study of periplocin and its two metabolites in rats by a validated LC-MS/MS method.

PubMed

Liu, Huaming; Zhang, Dandan; Tang, Zhidan; Sun, Mengjie; Azietaku, John Teye; Ouyang, Huizi; Chang, Yanxu; Wang, Meng; He, Jun; Gao, Xiumei

2018-05-29

Periplocin is a cardiac glycoside and has been used widely in the clinic for its cardiotonic, anti-inflammatory and anti-tumor effects. Though it was taken frequently by oral administration in clinic, there were no reports demonstrated that periplocin could be detected in vivo after an oral administration of periplocin, so it is badly need of searching the characteristic of periplocin in vivo after an oral administration. In this study, a sensitive and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to identify and quantify periplocin and its two metabolites in rat tissue after a single dosage of perplocin at 50 mg/kg. The results demonstrated that periplocin and its two metabolites were detected in all of the selected tissues, periplocin could be reach peak concentration quickly after administration, while periplocymarin and periplogenin reached maximum concentration more than 4.83 h after administration. The tissue distribution of analytes tended to be mostly in the liver, and higher analytes concentrations were found in the heart, liver, spleen, lung, kidney, but a small amount of chemical constituents were distributed into the brain. The consequences obtained using this method might provide a meaningful insight for the clinical investigations and applications. This article is protected by copyright. All rights reserved.

Preclinical evaluation of transcriptional targeting strategies for carcinoma of the breast in a tissue slice model system