Exposure to fine aerosol (PM2.5) is associated with loss of health and life expectancy, yet the m... more Exposure to fine aerosol (PM2.5) is associated with loss of health and life expectancy, yet the majority of the world's population lives far from in-situ monitors. Extreme events, such as major forest fires, are also often poorly monitored by in-situ stations. Satellite remote sensing offers an unparalleled level of global aerosol observation. The relationship between the column-integrated aerosol optical depth (AOD) provided by satellite and surface PM2.5 is, however, complicated by uncertainty in the aerosol vertical distribution, hygroscopicity, and optical properties. Chemical transport models give insight into the time-varying global distribution of these factors, allowing PM2.5 to be estimated directly from AOD. This talk will highlight some of the developments in remote sensing of surface fine aerosol and present recent findings based upon this work that range from the chronic exposure of populations around the world to the extreme acute levels experienced during the Mosc...
Calcification of bioprosthetic heart valves fabricated from glutaraldehyde (GA)-pretreated hetero... more Calcification of bioprosthetic heart valves fabricated from glutaraldehyde (GA)-pretreated heterograft tissue is frequently responsible for the clinical failure of these devices. Stentless bioprostheses fabricated from GA-fixed porcine aortic valves pose an important challenge in this regard, as pathologic calcification can affect not only the bioprosthetic cusps, but also the aortic wall segment. A synergistic approach was used to prevent bioprosthetic cusp and aortic wall calcification. Ethanol pretreatment of bioprosthetic heart valves was shown to inhibit cuspal calcification due to multiple mechanisms, including alterations of collagen structure and lipid extraction. AlCl3 pretreatment of bioprostheses to prevent calcification was also investigated; this alters elastin structure, inhibits alkaline phosphatase, and complexes with phosphoesters, thereby inhibiting aortic wall mineralization. Experimental data from rat subdermal implants and sheep mitral replacements showed succes...
To investigate the effect of microparticle size on gastrointestinal tissue uptake. Biodegradable ... more To investigate the effect of microparticle size on gastrointestinal tissue uptake. Biodegradable microparticles of various sizes using polylactic polyglycolic acid (50:50) co-polymer (100 nm, 500 nm, 1 micron, and 10 microns) and bovine serum albumin as a model protein were formulated by water-in-oil-in-water emulsion solvent evaporation technique. The uptake of microparticles was studied in rat in situ intestinal loop model and quantitatively analyzed for efficiency of uptake. In general, the efficiency of uptake of 100 nm size particles by the intestinal tissue was 15-250 fold higher compared to larger size microparticles. The efficiency of uptake was dependent on the type of tissue, such as Peyer's patch and non patch as well as on the location of the tissue collected i.e. duodenum or ileum. Depending on the size of microparticles, the Peyer's patch tissue had 2-200 fold higher uptake of particles than the non-patch tissue collected from the same region of the intestine. ...
The aim of the present study was to investigate the incorporation of plasmid DNA (pDNA) onto a co... more The aim of the present study was to investigate the incorporation of plasmid DNA (pDNA) onto a coronary stent by chemo-immunoconjugation for achieving site-specific gene delivery. Anti-DNA immunoglobulin M antibody was chemically linked onto collagen-coated stent by using N-succinimidyl-3-(2-pyridyldithiol)-propionate as cross-linker. pDNA was tethered on the antibody-immobilized stent by highly specific antigen-antibody affinity interaction. Radioactive-labeled antibody and pDNA were used to evaluate binding capacity and stability. A reporter plasmid pEGFP was tethered on the antibody-immobilized stents that was assessed in cell culture and in rabbit carotid model. The amount of antibody chemically linked on the stents was 15-fold higher than that of the control and its retention time was also significantly longer. The pEGFP-tethered stents had no detrimental effects on cell growth. In cell culture studies, numerous green fluorescent protein (GFP)-transfected cells were only found on the stent, which demonstrated high localization and efficiency of gene delivery. The overall GFP transfection efficiency in treated rabbit carotid arteries was 2.8 +/- 0.7% of the total cells. However, the rate of neointima transfection was 7.0 +/- 0.8% of total cells in this region. Importantly, no distal spreading of the vector was detected by polymerase chain reaction, either in distal organs or in the downstream segments of the stented arteries. For the first time, our group reports the successful use of anti-DNA antibody-immobilized metal stent as plasmid gene delivery system that possess high efficiency and site-specificity in vitro and in vivo.
Neuroblastoma (NB) is the most common and deadly solid tumor in children. The majority of NB pati... more Neuroblastoma (NB) is the most common and deadly solid tumor in children. The majority of NB patients have advanced stage disease with poor prognosis, so more effective, less toxic therapy is needed. We developed a novel nanocarrier-based strategy for tumor-targeted delivery of a prodrug of SN38, the active metabolite of irinotecan. We formulated ultrasmall-sized (<100 nm) biodegradable poly(lactide)-poly(ethylene glycol) based nanoparticles (NPs) containing SN38 conjugated to tocopherol succinate (SN38-TS). Alternative dosing schedules of SN38-TS NPs were compared to irinotecan. Comparison of SN38-TS NPs (2 doses) with irinotecan (20 doses) showed equivalent efficacy but no cures. Comparison of SN38-TS NPs (8, 8, and 16 doses, respectively) to irinotecan (40 doses) showed that all SN38-TS NP regimens were far superior to irinotecan, and "cures" were obtained in all NP arms. SN38-TS NP delivery resulted in 200× the amount of SN38 in NB tumors at 4 hr post-treatment, com...
Investigative ophthalmology & visual science, Jan 5, 2015
Purpose: The primary objective of the present study was to identify the kinetics and origin of oc... more Purpose: The primary objective of the present study was to identify the kinetics and origin of ocular infiltrating T cells in a pre-clinical model of graft-versus-host disease (GVHD) which induces eye tissue damage. Methods: GVHD was induced using an MHC-matched, minor histocompatibility mismatched hematopoietic stem cell transplant (HSCT) model. This approach - which utilized congenic and EGFP labeled donor populations, mimics a matched, clinically unrelated donor (MUD) cell transplant. Systemic and ocular GVHD were assessed at varying time points using clinical examination, intra-vital microscopy, immune phenotype via flow cytometric analyses and immunohistochemical staining. Results: Following transplant, we observed characteristic changes in GVHD associated immune phenotype as well as clinical signs present in recipients post-transplant. Notably, the kinetics of the systemic changes and the ocular damage paralleled what is observed clinically including damage to the cornea as we...
A randomized comparison of the relative efficacy and toxicity of daunorubicin (DNR) at 30 or 45 m... more A randomized comparison of the relative efficacy and toxicity of daunorubicin (DNR) at 30 or 45 mg/sq m or adriamycin (ADM) at 30 mg/sq m, given on the first 3 days of a 7-day continuous infusion of cytosine arabinoside (ara-C) at 100 mg/sq m/day, shows the outcome to be dependent on anthracycline, dose, and patient age. DNR 45 is significantly better than DNR 30 or ADM 30 for inducing complete remissions (CR) in patients younger than 60 yr, (72%, 59%, 58% CRs, respectively). DNR 30 is better than DNR 45 or ADM 30 for inducing CR in patients older than 60 yr (47%, 31%, 35%, respectively). There was a corresponding shift in the induction mortality for the age, dose, and anthracycline groups. Adriamycin was significantly more toxic to the gastrointestinal tract than daunorubicin. The duration of complete remission, with cyclic courses of maintenance therapy, was independent of the patient's age, the dose, or choice of anthracycline used in induction, and of whether the maintenance...
Experiments were carried out to investigate rat aortic allograft calcification using valved abdom... more Experiments were carried out to investigate rat aortic allograft calcification using valved abdominal aortic allografts. Results indicated that this was a potentially useful model for investigating fresh allograft calcification, as well as mineralization of glutaraldehyde-crosslinked valved allografts. Valve cusp results, however, were not comparable to those noted in large animal or human studies, while aortic wall calcification was more comparable. Calcification inhibitor investigations demonstrated that nearly complete inhibition of the calcification of the aortic wall of glutaraldehyde-crosslinked allografts was achieved using a number of individual inhibitors, including controlled release diphosphonates, and pretreatment with either ferric chloride or aluminum chloride. However, aminopropanehydroxydiphosphonate pretreatment was not efficacious, and sodium dodecyl sulfate pretreatment was only partially effective for inhibiting the aortic wall calcification in the glutaraldehyde-crosslinked allografts. It is concluded that valved aortic allografts in rats provide a useful model for investigating aortic wall (but not valve cusp) calcification and its inhibition.
MISR and MODIS aerosol product validation is a critical step needed before the products can be ap... more MISR and MODIS aerosol product validation is a critical step needed before the products can be applied to many environmental and climate-change questions. The process entails establishing uncertainties, assessing strengths and limitations, and reporting overall data quality. The MISR and MODIS instrument teams, as well as many other research groups, have performed such evaluations. A variety of methods have been employed, such as theoretical sensitivity studies, statistical comparisons with other satellite and suborbital data sets, and detailed, case-by-case analyses where coincident constraints from multiple sources were obtained. During the past ten years over which these instruments have been making observations, the exchange of ideas and results represented by this body of work has yielded better characterization of existing products, as well as algorithm upgrades. Having quantitative aerosol data of the sort provided by MISR and MODIS is pushing the limits of validation techniq...
Tissue contacting surfaces of medical devices initiate a host inflammatory response, characterize... more Tissue contacting surfaces of medical devices initiate a host inflammatory response, characterized by adsorption of blood proteins and inflammatory cells triggering the release of cytokines, reactive oxygen species (ROS) and reactive nitrogen species (RNS), in an attempt to clear or isolate the foreign object from the body. This normal host response contributes to device-associated pathophysiology and addressing device biocompatibility remains an unmet need. Although widespread attempts have been made to render the device surfaces unreactive, the establishment of a completely bioinert coating has been untenable and demonstrates the need to develop strategies based upon the molecular mechanisms that define the interaction between host cells and synthetic surfaces. In this review, we discuss a family of transmembrane receptors, known as immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptors, which show promise as potential targets to address aberrant biocompatibili...
In-stent restenosis presents a major complication of stent-based revascularization procedures wid... more In-stent restenosis presents a major complication of stent-based revascularization procedures widely used to re-establish blood flow through critically narrowed segments of coronary and peripheral arteries. Endovascular stents capable of tunable release of genes with anti-restenotic activity may present an alternative strategy to presently used drug-eluting stents. In order to attain clinical translation, gene-eluting stents must exhibit predictable kinetics of stent-immobilized gene vector release and site-specific transduction of vasculature, while avoiding an excessive inflammatory response typically associated with the polymer coatings used for physical entrapment of the vector. This paper describes a detailed methodology for coatless tethering of adenoviral gene vectors to stents based on a reversible binding of the adenoviral particles to polyallylamine bisphosphonate (PABT)-modified stainless steel surface via hydrolysable cross-linkers (HC). A family of bifunctional (amine- ...
An aerosol component of a new multiangle implementation of atmospheric correction (MAIAC) algorit... more An aerosol component of a new multiangle implementation of atmospheric correction (MAIAC) algorithm is presented. MAIAC is a generic algorithm developed for the Moderate Resolution Imaging Spectroradiometer (MODIS), which performs aerosol retrievals and atmospheric correction over both dark vegetated surfaces and bright deserts based on a time series analysis and image-based processing. The MAIAC look-up tables explicitly include surface bidirectional
Posttransplantation cyclophosphamide (PTCy) is an effective prophylaxis against graft-versus-host... more Posttransplantation cyclophosphamide (PTCy) is an effective prophylaxis against graft-versus-host disease (GVHD). However, it is unknown whether PTCy works singularly by eliminating alloreactive T cells via DNA alkylation or also by restoring the conventional (Tcon)/regulatory (Treg) T-cell balance. We studied the role of Tregs in PTCy-mediated GVHD prophylaxis in murine models of allogeneic blood or marrow transplantation (alloBMT). In 2 distinct MHC-matched alloBMT models, infusing Treg-depleted allografts abrogated the GVHD-prophylactic activity of PTCy. Using allografts in which Foxp3(+) Tregs could be selectively depleted in vivo, either pre- or post-PTCy ablation of donor thymus-derived Tregs (tTregs) abolished PTCy protection against GVHD. PTCy treatment was associated with relative preservation of donor Tregs. Experiments using combinations of Foxp3(-) Tcons and Foxp3(+) Tregs sorted from different Foxp3 reporter mice indicated that donor Treg persistence after PTCy treatmen...
Aortic allograft conduits and valves frequently undergo calcific degeneration. To study this prob... more Aortic allograft conduits and valves frequently undergo calcific degeneration. To study this problem, a rat subdermal model of nonvalved aortic wall allograft calcification was characterized, and experimental studies were carried out to test the hypothesis that aortic allograft preincubation in either amino-propanehydroxydiphosphonate (APDP) or AlCl3 would inhibit calcification in a rat subdermal model. Fresh thoracic aortas were harvested under sterile conditions from male Sprague-Dawley rats (350-400 g). APDP aortas were preincubated immediately in either 4 x 10(-3) mol/l, 4 x 10(-4) mol/l, or 4 x 10(-5) mol/l [14C] APDP (37 degrees C, pH 7.4) and controls were incubated in 0.05 mol/l HEPES buffer (pH 7.4, 37 degrees C, 30 min). Al3+ aortas were preincubated in either 10(-1) mol/l, 10(-2) mol/l, or 10(-3) mol/l AlCl3. Pretreated aortas were next implanted subdermally in weanling rats (3-week-old, male, Sprague-Dawley, 50-60 g) and retrieved after 21 days. Control explants retrieved at intervals up to 21 days demonstrated progressive calcification with bulk aortic allograft Ca2+ levels increasing from a preimplant value of 0.8 +/- 0.1 micrograms/mg to 129.8 +/- 12.9 micrograms/mg by 21 days. Light microscopy revealed that much of the calcium deposition was associated with elastin. Calcification was significantly inhibited in the 4 x 10(-3) mol/l and 4 x 10(-4) mol/l APDP preincubated groups was observed (Ca2+ = 0.70 +/- 0.15 micrograms/mg, 36.6 +/- 19.8 micrograms/mg, respectively versus 117.2 +/- 24.3 micrograms/mg, control). Inhibition of calcification in the groups preincubated in the two most concentrated AlCl3 solutions (Ca2+ = 13.9 +/- 4.9 micrograms/mg [10(-2) mol/l AlCl3], 36.6 +/- 7.1 micrograms/mg [10(-3) mol/l AlCl3], 171.0 +/- 13.2 micrograms/mg [control]) was also demonstrated. No adverse effects of either pretreatment, APDP, or AlCl3 were noted on bone or overall somatic growth.
Wolters Kluwer Health may email you for journal alerts and information, but is committed to maint... more Wolters Kluwer Health may email you for journal alerts and information, but is committed to maintaining your privacy and will not share your personal information without your express consent. For more information, please refer to our Privacy Policy. ... Skip Navigation Links Home &amp;amp;amp;gt; July/ ...
Journal of biomedical materials research. Part A, Jan 28, 2014
Bioprosthetic heart valves (BHV) fabricated from glutaraldehyde pretreated heterograft materials,... more Bioprosthetic heart valves (BHV) fabricated from glutaraldehyde pretreated heterograft materials, porcine aortic valves or bovine pericardium (BP), are widely used in cardiac surgery. BHV progressively fail in clinical use due to structural degeneration. Previously we reported that dityrosine, an oxidized amino acid, was present in failed clinical BP-BHV explants; unimplanted BP had no detectable dityrosine. In the same studies BP were demonstrated in vitro to be susceptible to oxidative damage, that could be mitigated with BP covalently modified with the antioxidant, 3-(4-hydroxy-3,5-di-tert-butylphenyl)propyl amine (DBP). The present studies compared in rat subdermal implants glutaraldehyde pretreated BP to BP modified with either DBP or the chemical reactions used to link DBP. All BP explants regardless of DBP demonstrated reduced hydroxyproline and increased digestibility by collagenase. However, the DBP-BP explants showed significant inhibition of reduced explant shrink tempera...
These studies investigate the involvement of the spleen in progenitor (PC) cell numbers and &... more These studies investigate the involvement of the spleen in progenitor (PC) cell numbers and &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;cross-talk&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; with the marrow compartment following syngeneic or allogeneic bone marrow transplantation (BMT) in sham or fully splenectomized mice. Intact recipient B6 mice were lethally irradiated prior to transplant with T cell-depleted bone marrow (BM-TCD). The kinetics of PC reconstitution following i.v. transplant consistently revealed a dramatic increase in splenic colony-forming unit interleukin-3 (CFU IL-3) and CFU (high proliferative potential-(HPP) levels between days 5 and 12 post-BMT. Direct injection of TCD-BM into the recipient marrow cavity did not alter this pattern of reconstitution in the splenic compartment. In contrast to spleens from normal adult B6 mice containing 0.9% and 0.6% of the total combined splenic and marrow committed (CFU IL-3) and primitive (CFU-HPP) progenitors, respectively, spleens of syngeneic BMT recipients at day 12 contained a 10-fold increase (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) over the progenitor levels in normal spleens. These splenic numbers decreased to normal, homeostatic levels by day 28 post-BMT. In contrast, the level of marrow CFU IL-3 progenitors continued to increase post-transplant, reaching near homeostatic levels by day 28 post-BMT. Interestingly, early seeding of 5- (and -6)carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled or green fluorescent protein (GFP) donor bone marrow cells (BMC) to the marrow compartment was not different in sham splenectomies or recipients splenectomized 14 days earlier. However, recipient splenectomy consistently resulted in significantly higher numbers of CFU IL-3 in the bone marrow during the first 2 weeks post-transplant compared to sham controls. These elevated levels exceeded the combined progenitor numbers of the splenic and marrow compartments of intact recipients. Notably, this increase in marrow progenitor activity in splenectomized recipients was observed after syngeneic as well as allogeneic BMT. Allogeneic transplants across major, or those limited to minor, histocompatibility antigen differences exhibited this increased marrow progenitor activity. Splenectomy performed 2 h post-transplant to assure &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;normal&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; marrow seeding also resulted in higher marrow progenitor activity. Thus, this &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;marrow response&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; to splenectomy is not induced by early &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;shunting&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; of infused BM cells to the marrow compartment. These results suggest that communication between the splenic and marrow compartments following syngeneic and allogeneic BMT exists during early hematopoietic reconstitution, one effect of which is to impact the compartmental distribution of donor progenitor cells. The role of the spleen on engraftment, chimerism, and tolerance in allogeneic BMT models are now under investigation.
Exposure to fine aerosol (PM2.5) is associated with loss of health and life expectancy, yet the m... more Exposure to fine aerosol (PM2.5) is associated with loss of health and life expectancy, yet the majority of the world's population lives far from in-situ monitors. Extreme events, such as major forest fires, are also often poorly monitored by in-situ stations. Satellite remote sensing offers an unparalleled level of global aerosol observation. The relationship between the column-integrated aerosol optical depth (AOD) provided by satellite and surface PM2.5 is, however, complicated by uncertainty in the aerosol vertical distribution, hygroscopicity, and optical properties. Chemical transport models give insight into the time-varying global distribution of these factors, allowing PM2.5 to be estimated directly from AOD. This talk will highlight some of the developments in remote sensing of surface fine aerosol and present recent findings based upon this work that range from the chronic exposure of populations around the world to the extreme acute levels experienced during the Mosc...
Calcification of bioprosthetic heart valves fabricated from glutaraldehyde (GA)-pretreated hetero... more Calcification of bioprosthetic heart valves fabricated from glutaraldehyde (GA)-pretreated heterograft tissue is frequently responsible for the clinical failure of these devices. Stentless bioprostheses fabricated from GA-fixed porcine aortic valves pose an important challenge in this regard, as pathologic calcification can affect not only the bioprosthetic cusps, but also the aortic wall segment. A synergistic approach was used to prevent bioprosthetic cusp and aortic wall calcification. Ethanol pretreatment of bioprosthetic heart valves was shown to inhibit cuspal calcification due to multiple mechanisms, including alterations of collagen structure and lipid extraction. AlCl3 pretreatment of bioprostheses to prevent calcification was also investigated; this alters elastin structure, inhibits alkaline phosphatase, and complexes with phosphoesters, thereby inhibiting aortic wall mineralization. Experimental data from rat subdermal implants and sheep mitral replacements showed succes...
To investigate the effect of microparticle size on gastrointestinal tissue uptake. Biodegradable ... more To investigate the effect of microparticle size on gastrointestinal tissue uptake. Biodegradable microparticles of various sizes using polylactic polyglycolic acid (50:50) co-polymer (100 nm, 500 nm, 1 micron, and 10 microns) and bovine serum albumin as a model protein were formulated by water-in-oil-in-water emulsion solvent evaporation technique. The uptake of microparticles was studied in rat in situ intestinal loop model and quantitatively analyzed for efficiency of uptake. In general, the efficiency of uptake of 100 nm size particles by the intestinal tissue was 15-250 fold higher compared to larger size microparticles. The efficiency of uptake was dependent on the type of tissue, such as Peyer's patch and non patch as well as on the location of the tissue collected i.e. duodenum or ileum. Depending on the size of microparticles, the Peyer's patch tissue had 2-200 fold higher uptake of particles than the non-patch tissue collected from the same region of the intestine. ...
The aim of the present study was to investigate the incorporation of plasmid DNA (pDNA) onto a co... more The aim of the present study was to investigate the incorporation of plasmid DNA (pDNA) onto a coronary stent by chemo-immunoconjugation for achieving site-specific gene delivery. Anti-DNA immunoglobulin M antibody was chemically linked onto collagen-coated stent by using N-succinimidyl-3-(2-pyridyldithiol)-propionate as cross-linker. pDNA was tethered on the antibody-immobilized stent by highly specific antigen-antibody affinity interaction. Radioactive-labeled antibody and pDNA were used to evaluate binding capacity and stability. A reporter plasmid pEGFP was tethered on the antibody-immobilized stents that was assessed in cell culture and in rabbit carotid model. The amount of antibody chemically linked on the stents was 15-fold higher than that of the control and its retention time was also significantly longer. The pEGFP-tethered stents had no detrimental effects on cell growth. In cell culture studies, numerous green fluorescent protein (GFP)-transfected cells were only found on the stent, which demonstrated high localization and efficiency of gene delivery. The overall GFP transfection efficiency in treated rabbit carotid arteries was 2.8 +/- 0.7% of the total cells. However, the rate of neointima transfection was 7.0 +/- 0.8% of total cells in this region. Importantly, no distal spreading of the vector was detected by polymerase chain reaction, either in distal organs or in the downstream segments of the stented arteries. For the first time, our group reports the successful use of anti-DNA antibody-immobilized metal stent as plasmid gene delivery system that possess high efficiency and site-specificity in vitro and in vivo.
Neuroblastoma (NB) is the most common and deadly solid tumor in children. The majority of NB pati... more Neuroblastoma (NB) is the most common and deadly solid tumor in children. The majority of NB patients have advanced stage disease with poor prognosis, so more effective, less toxic therapy is needed. We developed a novel nanocarrier-based strategy for tumor-targeted delivery of a prodrug of SN38, the active metabolite of irinotecan. We formulated ultrasmall-sized (<100 nm) biodegradable poly(lactide)-poly(ethylene glycol) based nanoparticles (NPs) containing SN38 conjugated to tocopherol succinate (SN38-TS). Alternative dosing schedules of SN38-TS NPs were compared to irinotecan. Comparison of SN38-TS NPs (2 doses) with irinotecan (20 doses) showed equivalent efficacy but no cures. Comparison of SN38-TS NPs (8, 8, and 16 doses, respectively) to irinotecan (40 doses) showed that all SN38-TS NP regimens were far superior to irinotecan, and "cures" were obtained in all NP arms. SN38-TS NP delivery resulted in 200× the amount of SN38 in NB tumors at 4 hr post-treatment, com...
Investigative ophthalmology & visual science, Jan 5, 2015
Purpose: The primary objective of the present study was to identify the kinetics and origin of oc... more Purpose: The primary objective of the present study was to identify the kinetics and origin of ocular infiltrating T cells in a pre-clinical model of graft-versus-host disease (GVHD) which induces eye tissue damage. Methods: GVHD was induced using an MHC-matched, minor histocompatibility mismatched hematopoietic stem cell transplant (HSCT) model. This approach - which utilized congenic and EGFP labeled donor populations, mimics a matched, clinically unrelated donor (MUD) cell transplant. Systemic and ocular GVHD were assessed at varying time points using clinical examination, intra-vital microscopy, immune phenotype via flow cytometric analyses and immunohistochemical staining. Results: Following transplant, we observed characteristic changes in GVHD associated immune phenotype as well as clinical signs present in recipients post-transplant. Notably, the kinetics of the systemic changes and the ocular damage paralleled what is observed clinically including damage to the cornea as we...
A randomized comparison of the relative efficacy and toxicity of daunorubicin (DNR) at 30 or 45 m... more A randomized comparison of the relative efficacy and toxicity of daunorubicin (DNR) at 30 or 45 mg/sq m or adriamycin (ADM) at 30 mg/sq m, given on the first 3 days of a 7-day continuous infusion of cytosine arabinoside (ara-C) at 100 mg/sq m/day, shows the outcome to be dependent on anthracycline, dose, and patient age. DNR 45 is significantly better than DNR 30 or ADM 30 for inducing complete remissions (CR) in patients younger than 60 yr, (72%, 59%, 58% CRs, respectively). DNR 30 is better than DNR 45 or ADM 30 for inducing CR in patients older than 60 yr (47%, 31%, 35%, respectively). There was a corresponding shift in the induction mortality for the age, dose, and anthracycline groups. Adriamycin was significantly more toxic to the gastrointestinal tract than daunorubicin. The duration of complete remission, with cyclic courses of maintenance therapy, was independent of the patient's age, the dose, or choice of anthracycline used in induction, and of whether the maintenance...
Experiments were carried out to investigate rat aortic allograft calcification using valved abdom... more Experiments were carried out to investigate rat aortic allograft calcification using valved abdominal aortic allografts. Results indicated that this was a potentially useful model for investigating fresh allograft calcification, as well as mineralization of glutaraldehyde-crosslinked valved allografts. Valve cusp results, however, were not comparable to those noted in large animal or human studies, while aortic wall calcification was more comparable. Calcification inhibitor investigations demonstrated that nearly complete inhibition of the calcification of the aortic wall of glutaraldehyde-crosslinked allografts was achieved using a number of individual inhibitors, including controlled release diphosphonates, and pretreatment with either ferric chloride or aluminum chloride. However, aminopropanehydroxydiphosphonate pretreatment was not efficacious, and sodium dodecyl sulfate pretreatment was only partially effective for inhibiting the aortic wall calcification in the glutaraldehyde-crosslinked allografts. It is concluded that valved aortic allografts in rats provide a useful model for investigating aortic wall (but not valve cusp) calcification and its inhibition.
MISR and MODIS aerosol product validation is a critical step needed before the products can be ap... more MISR and MODIS aerosol product validation is a critical step needed before the products can be applied to many environmental and climate-change questions. The process entails establishing uncertainties, assessing strengths and limitations, and reporting overall data quality. The MISR and MODIS instrument teams, as well as many other research groups, have performed such evaluations. A variety of methods have been employed, such as theoretical sensitivity studies, statistical comparisons with other satellite and suborbital data sets, and detailed, case-by-case analyses where coincident constraints from multiple sources were obtained. During the past ten years over which these instruments have been making observations, the exchange of ideas and results represented by this body of work has yielded better characterization of existing products, as well as algorithm upgrades. Having quantitative aerosol data of the sort provided by MISR and MODIS is pushing the limits of validation techniq...
Tissue contacting surfaces of medical devices initiate a host inflammatory response, characterize... more Tissue contacting surfaces of medical devices initiate a host inflammatory response, characterized by adsorption of blood proteins and inflammatory cells triggering the release of cytokines, reactive oxygen species (ROS) and reactive nitrogen species (RNS), in an attempt to clear or isolate the foreign object from the body. This normal host response contributes to device-associated pathophysiology and addressing device biocompatibility remains an unmet need. Although widespread attempts have been made to render the device surfaces unreactive, the establishment of a completely bioinert coating has been untenable and demonstrates the need to develop strategies based upon the molecular mechanisms that define the interaction between host cells and synthetic surfaces. In this review, we discuss a family of transmembrane receptors, known as immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptors, which show promise as potential targets to address aberrant biocompatibili...
In-stent restenosis presents a major complication of stent-based revascularization procedures wid... more In-stent restenosis presents a major complication of stent-based revascularization procedures widely used to re-establish blood flow through critically narrowed segments of coronary and peripheral arteries. Endovascular stents capable of tunable release of genes with anti-restenotic activity may present an alternative strategy to presently used drug-eluting stents. In order to attain clinical translation, gene-eluting stents must exhibit predictable kinetics of stent-immobilized gene vector release and site-specific transduction of vasculature, while avoiding an excessive inflammatory response typically associated with the polymer coatings used for physical entrapment of the vector. This paper describes a detailed methodology for coatless tethering of adenoviral gene vectors to stents based on a reversible binding of the adenoviral particles to polyallylamine bisphosphonate (PABT)-modified stainless steel surface via hydrolysable cross-linkers (HC). A family of bifunctional (amine- ...
An aerosol component of a new multiangle implementation of atmospheric correction (MAIAC) algorit... more An aerosol component of a new multiangle implementation of atmospheric correction (MAIAC) algorithm is presented. MAIAC is a generic algorithm developed for the Moderate Resolution Imaging Spectroradiometer (MODIS), which performs aerosol retrievals and atmospheric correction over both dark vegetated surfaces and bright deserts based on a time series analysis and image-based processing. The MAIAC look-up tables explicitly include surface bidirectional
Posttransplantation cyclophosphamide (PTCy) is an effective prophylaxis against graft-versus-host... more Posttransplantation cyclophosphamide (PTCy) is an effective prophylaxis against graft-versus-host disease (GVHD). However, it is unknown whether PTCy works singularly by eliminating alloreactive T cells via DNA alkylation or also by restoring the conventional (Tcon)/regulatory (Treg) T-cell balance. We studied the role of Tregs in PTCy-mediated GVHD prophylaxis in murine models of allogeneic blood or marrow transplantation (alloBMT). In 2 distinct MHC-matched alloBMT models, infusing Treg-depleted allografts abrogated the GVHD-prophylactic activity of PTCy. Using allografts in which Foxp3(+) Tregs could be selectively depleted in vivo, either pre- or post-PTCy ablation of donor thymus-derived Tregs (tTregs) abolished PTCy protection against GVHD. PTCy treatment was associated with relative preservation of donor Tregs. Experiments using combinations of Foxp3(-) Tcons and Foxp3(+) Tregs sorted from different Foxp3 reporter mice indicated that donor Treg persistence after PTCy treatmen...
Aortic allograft conduits and valves frequently undergo calcific degeneration. To study this prob... more Aortic allograft conduits and valves frequently undergo calcific degeneration. To study this problem, a rat subdermal model of nonvalved aortic wall allograft calcification was characterized, and experimental studies were carried out to test the hypothesis that aortic allograft preincubation in either amino-propanehydroxydiphosphonate (APDP) or AlCl3 would inhibit calcification in a rat subdermal model. Fresh thoracic aortas were harvested under sterile conditions from male Sprague-Dawley rats (350-400 g). APDP aortas were preincubated immediately in either 4 x 10(-3) mol/l, 4 x 10(-4) mol/l, or 4 x 10(-5) mol/l [14C] APDP (37 degrees C, pH 7.4) and controls were incubated in 0.05 mol/l HEPES buffer (pH 7.4, 37 degrees C, 30 min). Al3+ aortas were preincubated in either 10(-1) mol/l, 10(-2) mol/l, or 10(-3) mol/l AlCl3. Pretreated aortas were next implanted subdermally in weanling rats (3-week-old, male, Sprague-Dawley, 50-60 g) and retrieved after 21 days. Control explants retrieved at intervals up to 21 days demonstrated progressive calcification with bulk aortic allograft Ca2+ levels increasing from a preimplant value of 0.8 +/- 0.1 micrograms/mg to 129.8 +/- 12.9 micrograms/mg by 21 days. Light microscopy revealed that much of the calcium deposition was associated with elastin. Calcification was significantly inhibited in the 4 x 10(-3) mol/l and 4 x 10(-4) mol/l APDP preincubated groups was observed (Ca2+ = 0.70 +/- 0.15 micrograms/mg, 36.6 +/- 19.8 micrograms/mg, respectively versus 117.2 +/- 24.3 micrograms/mg, control). Inhibition of calcification in the groups preincubated in the two most concentrated AlCl3 solutions (Ca2+ = 13.9 +/- 4.9 micrograms/mg [10(-2) mol/l AlCl3], 36.6 +/- 7.1 micrograms/mg [10(-3) mol/l AlCl3], 171.0 +/- 13.2 micrograms/mg [control]) was also demonstrated. No adverse effects of either pretreatment, APDP, or AlCl3 were noted on bone or overall somatic growth.
Wolters Kluwer Health may email you for journal alerts and information, but is committed to maint... more Wolters Kluwer Health may email you for journal alerts and information, but is committed to maintaining your privacy and will not share your personal information without your express consent. For more information, please refer to our Privacy Policy. ... Skip Navigation Links Home &amp;amp;amp;gt; July/ ...
Journal of biomedical materials research. Part A, Jan 28, 2014
Bioprosthetic heart valves (BHV) fabricated from glutaraldehyde pretreated heterograft materials,... more Bioprosthetic heart valves (BHV) fabricated from glutaraldehyde pretreated heterograft materials, porcine aortic valves or bovine pericardium (BP), are widely used in cardiac surgery. BHV progressively fail in clinical use due to structural degeneration. Previously we reported that dityrosine, an oxidized amino acid, was present in failed clinical BP-BHV explants; unimplanted BP had no detectable dityrosine. In the same studies BP were demonstrated in vitro to be susceptible to oxidative damage, that could be mitigated with BP covalently modified with the antioxidant, 3-(4-hydroxy-3,5-di-tert-butylphenyl)propyl amine (DBP). The present studies compared in rat subdermal implants glutaraldehyde pretreated BP to BP modified with either DBP or the chemical reactions used to link DBP. All BP explants regardless of DBP demonstrated reduced hydroxyproline and increased digestibility by collagenase. However, the DBP-BP explants showed significant inhibition of reduced explant shrink tempera...
These studies investigate the involvement of the spleen in progenitor (PC) cell numbers and &... more These studies investigate the involvement of the spleen in progenitor (PC) cell numbers and &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;cross-talk&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; with the marrow compartment following syngeneic or allogeneic bone marrow transplantation (BMT) in sham or fully splenectomized mice. Intact recipient B6 mice were lethally irradiated prior to transplant with T cell-depleted bone marrow (BM-TCD). The kinetics of PC reconstitution following i.v. transplant consistently revealed a dramatic increase in splenic colony-forming unit interleukin-3 (CFU IL-3) and CFU (high proliferative potential-(HPP) levels between days 5 and 12 post-BMT. Direct injection of TCD-BM into the recipient marrow cavity did not alter this pattern of reconstitution in the splenic compartment. In contrast to spleens from normal adult B6 mice containing 0.9% and 0.6% of the total combined splenic and marrow committed (CFU IL-3) and primitive (CFU-HPP) progenitors, respectively, spleens of syngeneic BMT recipients at day 12 contained a 10-fold increase (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) over the progenitor levels in normal spleens. These splenic numbers decreased to normal, homeostatic levels by day 28 post-BMT. In contrast, the level of marrow CFU IL-3 progenitors continued to increase post-transplant, reaching near homeostatic levels by day 28 post-BMT. Interestingly, early seeding of 5- (and -6)carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled or green fluorescent protein (GFP) donor bone marrow cells (BMC) to the marrow compartment was not different in sham splenectomies or recipients splenectomized 14 days earlier. However, recipient splenectomy consistently resulted in significantly higher numbers of CFU IL-3 in the bone marrow during the first 2 weeks post-transplant compared to sham controls. These elevated levels exceeded the combined progenitor numbers of the splenic and marrow compartments of intact recipients. Notably, this increase in marrow progenitor activity in splenectomized recipients was observed after syngeneic as well as allogeneic BMT. Allogeneic transplants across major, or those limited to minor, histocompatibility antigen differences exhibited this increased marrow progenitor activity. Splenectomy performed 2 h post-transplant to assure &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;normal&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; marrow seeding also resulted in higher marrow progenitor activity. Thus, this &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;marrow response&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; to splenectomy is not induced by early &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;shunting&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; of infused BM cells to the marrow compartment. These results suggest that communication between the splenic and marrow compartments following syngeneic and allogeneic BMT exists during early hematopoietic reconstitution, one effect of which is to impact the compartmental distribution of donor progenitor cells. The role of the spleen on engraftment, chimerism, and tolerance in allogeneic BMT models are now under investigation.
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