The need to pursue and publish clinical trials in nanomedicine

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87037/1/141_ftp.pd

Guest Editorial

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63108/1/105072501750159633.pd

The Role of Apoptosis in Thyroid Autoimmunity

There is increasing evidence showing that apoptosis plays a role in the development of the autoimmune thyroid diseases—Hashimoto's (lymphocytic) thyroiditis (HT) and Graves' disease (GD). The immune pathogenesis of HT and GD is not yet fully understood, but evidence points toward several steps. A defect in CD4+CD25+ T regulatory cells breaks the immunological tolerance of the host and induces an abnormal production of cytokines, which facilitates the initiation of apoptosis. Though apoptosis appears to play a role in the pathogenesis of both HT and GD, the mechanisms that mediate these processes appear different. The induction of apoptosis in HT results in the destruction of thyrocytes, while apoptosis in the GD leads to damage of thyroid-infiltrating lymphocytes. The differences in the apoptotic mechanisms produce two very different forms of thyroid autoimmune responses, eventually developing into HT and GD, respectively.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63177/1/thy.2007.0208.pd

No Apparent Damage in the Thyroid of Transgenic Mice Expressing Antiapoptotic FLIP

FLIP is an antiapoptotic protein that has been demonstrated to play an important role in inflammation, cancer, and autoimmune diseases. However, it is not known whether increased expression of FLIP (FLICE inhibitory protein) in thyrocytes would alter the development of the thyroid and/or pathogenesis of thyroiditis. To examine the effects of overexpression of this antiapoptotic molecule on the thyroid, we have developed transgenic mouse lines that specifically express FLIP in thyrocytes. A DNA construct designed with an in-frame coding sequence for the E8 protein, a viral FLIP, was put under the control of the thyroglobulin (Tg) promoter (the Tg-FLIP transgene). In 8 of 12 resultant transgenic mouse lines, FLIP expression in thyrocytes driven by the Tg promoter was documented, and confirmed at RNA and protein levels. These Tg-FLIP transgenic mice were monitored for 1 year. Throughout the entire observation period, the transgenic mice remained alive and healthy without evidence of thyroid dysfunction. Adult mice were able to breed. Histologic examination of thyroids obtained at various time points did not reveal significant differences between transgenic mice and their control littermates. Therefore, transgenic mice with thyrocyte-specific expression of FLIP have normal thyroid development with no significant changes in thyroid cell death or proliferation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63191/1/thy.2006.16.1.pd

Computer Components and Systems

Contains reports on two research projects.U. S. Navy Bureau of Ships under Contract NObsr 7760

Efficient Transfer of Genes into Murine Cardiac Grafts by Starburst Polyamidoamine Dendrimers

Overview summary Plasmid-mediated gene therapy has been used to deliver immunosuppressive molecules into allografts to prolong graft survival. However, direct injection of naked plasmid DNA is inefficient because transgene expression is low and transient. This study investigated the ability of Starburst dendrimers to augment plasmid-mediated gene transfer efficiency in a murine cardiac transplantation model. The results demonstrate that dendrimers increased the efficiency of transfer and expression of exogenous DNA in cardiac grafts. Improved expression of an immunosuppressive cytokine viral interleukin-10 (vIL-10) by dendrimers significantly prolonged allograft survival. The dose of DNA, the charge ratio of DNA to dendrimer, and the size generation of the dendrimers were all critical for prolongation of allograft survival. Thus, the use of the Starburst dendrimer as a carrier molecule for plasmid-mediated gene transfer improved the efficiency of transfer and expression, providing further therapeutic value for treatment of cardiac allograft rejection.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63156/1/hum.1998.9.4-553.pd

T-lymphocyte activation in adult-onset idiopathic hypoparathyroidism

: Patients with adult-onset idiopathic hypoparathyroidism (AOIH) often have antibodies against the parathyroid glands and other tissues, suggestive of immune activation. The purpose of this study was to determine whether T-cell activation is also a component of the endocrine disease.: We identified eight patients with idiopathic hypoparathyroidism diagnosed after the age of 30 years at two tertiary care centers and evaluated peripheral blood lymphocyte subset phenotype frequencies using monoclonal antibodies and flow cytometry. Control subjects were 13 patients with Graves' disease (five thyrotoxic and eight euthyroid) and 110 healthy volunteers. In two of the patients with AOIH, we also determined the mitogenic response to parathyroid cell membranes in peripheral lymphocytes.: Patients with AOIH had higher than normal frequencies of the following phenotypes (p : Generalized T-cell activation represents a novel feature associated with AOIH. Although we could not demonstrate parathyroid-specific lymphocyte clonal expansion, these data are suggestive of a generalized immune disturbance possibly related to autoimmunity, in which one of the manifestations is hypoparathyroidism.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30341/1/0000743.pd

Synthesis, characterization, and manipulation of dendrimer-stabilized iron sulfide nanoparticles

FeS nanoparticles (NPs) were synthesized using ethylenediamine core poly(amidoamine) (PAMAM) dendrimers of generation 4 terminated with amino (G4·NH2), hydroxyl (G4·NGlyOH), and carboxyl (G4·SAH) groups, respectively, as stabilizers. These dendrimer-stabilized FeS NPs (FeS DSNPs) were characterized by ultraviolet–visible (UV–vis) spectrometry, zeta-potential measurements, and transmission electron microscopy (TEM). Deposition of FeS NPs onto mesoporous silica gel microparticles was attempted using two approaches: (A) direct coating of {FeS–G4·NH2} DSNPs onto silica particles; and (B) using G4·NH2-coated silica particles to incorporate Fe2+ ions for the subsequent formation of FeS NPs. Scanning electron microscopy (SEM) studies show that approach (B) was much more efficient in the incorporation of FeS NPs than approach (A). Such preparation and manipulation of FeS DSNPs provides a unique strategy for fabricating various reactive nanoplatforms for environmental remediation applications.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/49224/2/nano6_18_005.pd

Nasal Immunization with a Recombinant HIV gp120 and Nanoemulsion Adjuvant Produces Th1 Polarized Responses and Neutralizing Antibodies to Primary HIV Type 1 Isolates

ABSTRACT Epidemiological and experimental data suggest that both robust neutralizing antibodies and potent cellular responses play important roles in controlling primary HIV-1 infection. In this study we have investigated the induction of systemic and mucosal immune responses to HIV gp120 monomer immunogen administered intranasally in a novel, oil-in-water nanoemulsion (NE) adjuvant. Mice and guinea pigs intranasally immunized by the application of recombinant HIV gp120 antigen mixed in NE demonstrated robust serum anti-gp120 IgG, as well as bronchial, vaginal, and serum anti-gp120 IgA in mice. The serum of these animals demonstrated antibodies that cross-reacted with heterologous serotypes of gp120 and had significant neutralizing activity against two clade-B laboratory strains of HIV (HIVBaL and HIVSF162) and five primary HIV-1 isolates. The analysis of gp120-specific CTL proliferation, INF-γ induction, and prevalence of anti-gp120 IgG2 subclass antibodies indicated that nasal vaccination in NE also induced systemic, Th1-polarized cellular immune responses. This study suggests that NE should be evaluated as a mucosal adjuvant for multivalent HIV vaccines.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63251/1/aid.2007.0148.pd

The fungicidal activity of novel nanoemulsion (X8W 60 PC) against clinically important yeast and filamentous fungi

Surfactant nanoemulsions are water in oil preparations that proved to have a broad spectrum biocidal activity against a variety of microorganisms including Gram-positive and Gram-negative bacteria, spores and enveloped viruses. These preparations are non-toxic to the skin, mucous membrane and gastrointestinal tissues at biocidal concentrations. In this study, 0.1% of the nanoemulsion designated X8W 60 PC has shown fungicidal activity against yeast including Candida albicans and C. tropicalis in 15 minutes. C. tropicalis was more sensitive than C. albicans , which required a longer time or a higher concentration of the nanoemulsion to achieve killing. Neutral to slightly alkaline pH was more effective in killing the yeast cells than acidic pH. Using the minimum inhibitory concentration assay, 0.08% of the nanoemulsion was inhibitory to C. albicans , and parapsilosis and filamentous fungi including Microsporum gypseum , Trichophyton mentagrophytes , Trichophyton rubrum , Aspergillus fumigatus and Fusarium oxysporum .None of the individual ingredients was as effective a fungicidal as the nanoemulsion at equivalent concentration. This shows that the nanoemulsion structure is an important factor in the anti-fungal activity. The X8W 60 PC has great potential as a topical anti-fungal agent and further investigation into the mechanism of fungicidal action is warranted.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43273/1/11046_2004_Article_5096122.pd