On deformations of pasting diagrams, II

We continue the development of the infinitesimal deformation theory of pasting diagrams of k-linear categories begun in TAC, Vol 22, #2. In that article the standard result that all obstructions are cocycles was established only for the elementary, composition-free parts of pasting diagrams. In the present work we give a proof for pasting diagrams in general. As tools we use the method developed by Shrestha of simultaneously representing formulas for obstructions, along with the corresponding cocycle and cobounding conditions by suitably labeled polygons, giving a rigorous exposition of the previously heuristic method; and deformations of pasting diagrams in which some cells are required to be deformed trivially

Cells as delivery vehicles for cancer therapeutics

Cell-based therapeutics have advanced significantly over the past decade and are poised to become a major pillar of modern medicine. Three cell types in particular have been studied in detail for their ability to home to tumors and to deliver a variety of different payloads. Neural stem cells, mesenchymal stem cells and monocytes have each been shown to have great potential as future delivery systems for cancer therapy. A variety of other cell types have also been studied. These results demonstrate that the field of cell-based therapeutics will only continue to grow

Cell Based Drug Delivery: Micrococcus luteus Loaded Neutrophils as Chlorhexidine Delivery Vehicles in a Mouse Model of Liver Abscesses in Cattle

Citation: Wendel, S. O., Menon, S., Alshetaiwi, H., Shrestha, T. B., Chlebanowski, L., Hsu, W. W., . . . Troyer, D. L. (2015). Cell Based Drug Delivery: Micrococcus luteus Loaded Neutrophils as Chlorhexidine Delivery Vehicles in a Mouse Model of Liver Abscesses in Cattle. Plos One, 10(5), 13. doi:10.1371/journal.pone.0128144The recent WHO report on antibiotic resistances shows a dramatic increase of microbial resistance against antibiotics. With only a few new antibiotics in the pipeline, a different drug delivery approach is urgently needed. We have obtained evidence demonstrating the effectiveness of a cell based drug delivery system that utilizes the innate immune system as targeting carrier for antibacterial drugs. In this study we show the efficient loading of neutrophil granulocytes with chlorhexidine and the complete killing of E. coli as well as Fusobacterium necrophorum in in-vitro studies. Fusobacterium necrophorum causes hepatic abscesses in cattle fed high grain diets. We also show in a mouse model that this delivery system targets infections of F. necrophorum in the liver and reduces the bacterial burden by an order of magnitude from approximately 2.10(6) to 1.10(5)

Heterocycles for life-sciences applications and information storage

Doctor of PhilosophyDepartment of ChemistryStefan H. BossmannThe photochromic spirodihydroindolizine/betaine (DHI/B) system has been reinvestigated applying picosecond, microsecond, stationary absorption measurements, and NMR-kinetics. The first surprise was that the electronic structure of the betaines is quite different than commonly assumed. The photochemical ring-opening of DHIs to betaines is a conrotatory 1,5 electrocyclic reaction, as picosecond absorption spectroscopy confirms. The (disrotatory) thermal ring-closing occurs from the cisoid betaine. The lifetime of the transoid betaine is 60 s at 300 K, whereas the lifetime of the cisoid isomer is of the order of 250 microseconds. According to these results, the electrocyclic back reaction of the betaines to the DHI is NOT rate determining, as previously thought, but the cisoid-transoid-isomerization of the betaine. Although the presence of a second nitrogen atom increases the photostability of the spirodihydroindolizine-pyridazine/betaine-system remarkably, the photochemical reaction mechanism appears to be exactly the same for spirodihydroindolizine-pyridazine/betaine-system. A nondestructive photoswitch or an information recording systems has been explored using styryl-quinolyldihydroindolizines. Both isomers DHI and betaine are fluorescent. When the blue betaine is stabilized in a thin polymethyl methacrylate (PMMA) matrix, it is stable for several hours even in room temperature and very stable at 77K. Although irradiation of visible light = 532 nm allows the photo-induced reaction of the Betaine back to the DHI, a nondestructive read-out can be performed at λ = 645 nm upon excitation with λ = 580 nm. Image recording (write) and read-out, as well as information storage (at 77K) have been demonstrated. Charged and maleimide-functionalized DHI/B systems have beed synthesized for use as photochemical gates of the mycobacterial channel porin MspA. Positively charged and maleimide functionalized DHI groups that were attached to the DHI/B-system permit the binding of the photoswitch to selective positions in the channel proteins due to the presence of a cysteine moiety. An inexpensive new method for the large scale synthesis of coelenterazine is developed. A modified Negishi coupling reaction is used to make pyrazine intermediates from aminopyrazine as an economical starting material. This method permits the use of up to 1g coelenterazine per kg body weight and day, which turns the renilla transfected stem cells into powerful light sources

Comparison study on some classical lack-of-fit tests in regression models

Master of ScienceDepartment of StatisticsWeixing SongThe relationship between a random variable and a random vector is often investigated through the regression modeling. Because of its relative simplicity and ease of interpretation, a particular parametric form is often assumed for the regression function. If the pre-specified function form truly reflects the truth, then the resulting estimators and inference procedures would be reliable and efficient. But if the regression function does not represent the true relationship between the response and the predictors, then the inference results might be very misleading. Therefore, lack-of-fit test should be an indispensable part in regression modeling. This report compares the finite sample performance of several classical lack-of-fit tests in regression models via simulation studies. It has three chapters. The conception of the lack-of-fit test, together with its basic setup, is briefly introduced in Chapter 1; then several classical lack-of-fit test procedures are discussed in Chapter 2; finally, thorough simulation studies are conducted in Chapter 3 to assess the finite sample performance of each procedure introduced in Chapter 2. Some conclusions are also summarized in Chapter 3. A list of MATLAB codes that are used for the simulation studies is given in the appendix

Algebraic deformation of a monoidal category

Doctor of PhilosophyDepartment of MathematicsDavid YetterThis dissertation begins the development of the deformation theorem of monoidal categories which accounts for the function that all arrow-valued operations, composition, the arrow part of the monoidal product, and structural natural transformation are deformed. The first chapter is review of algebra deformation theory. It includes the Hochschild complex of an algebra, Gerstenhaber's deformation theory of rings and algebras, Yetter's deformation theory of a monoidal category, Gerstenhaber and Schack's bialgebra deformation theory and Markl and Shnider's deformation theory for Drinfel'd algebras. The second chapter examines deformations of a small $k$-linear monoidal category. It examines deformations beginning with a naive computational approach to discover that as in Markl and Shnider's theory for Drinfel'd algebras, deformations of monoidal categories are governed by the cohomology of a multicomplex. The standard results concerning first order deformations are established. Obstructions are shown to be cocycles in the special case of strict monoidal categories when one of composition or tensor or the associator is left undeformed. At the end there is a brief conclusion with conjectures

Luminol-based bioluminescence imaging of mouse mammary tumors

Polymorphonuclear neutrophils (PMNs) are the most abundant circulating blood leukocytes. They are part of the innate immune system and provide a first line of defense by migrating toward areas of inflammation in response to chemical signals released from the site. Some solid tumors, such as breast cancer, also cause recruitment and activation of PMNs and release of myeloperoxidase. In this study, we demonstrate that administration of luminol to mice that have been transplanted with 4T1 mammary tumor cells permits the detection of myeloperoxidase activity, and consequently, the location of the tumor. Luminol allowed detection of activated PMNs only two days after cancer cell transplantation, even though tumors were not yet palpable. In conclusion, luminol-bioluminescence imaging (BLI) can provide a pathway towards detection of solid tumors at an early stage in preclinical tumor models

Interleukin-1 beta and transforming growth factor-beta cooperate to induce neurosphere formation and increase tumorigenicity of adherent LN-229 glioma cells

Introduction: Glioma stem cells (GSCs) have the property of self-renewal and appear to be a driving force for the initiation and recurrence of gliomas. We recently found that the human tumorigenic LN-229 glioma cell line failed to form neurospheres in serum-free conditions and generated mostly small tumors in vivo, suggesting that either LN-229 GSCs are not active in these conditions or GSCs are absent in the LN-229 cell line. Methods: Using self-renewal assay, soft-agar colony assay, cell proliferation assay, invasion assay, real time PCR analysis, ELISA and in vivo tumorigenic assay, we investigated the effects of interleukin (IL)-1beta and transforming growth factor (TGF)-beta on the development of GSCs from LN-229 cells. Results: Here, we demonstrate that the combination of IL-1beta and TGF-beta can induce LN-229 cells to form neurospheres in serum-free medium. IL-1beta/TGF-beta-induced neurospheres display up-regulated expression of stemness factor genes (nestin, Bmi-1, Notch-2 and LIF), and increased invasiveness, drug resistance and tumor growth in vivo: hallmarks of GSCs. These results indicate that IL-1beta and TGF-beta cooperate to induce a GSC phenotype in the LN-229 cell line. Induction of nestin, LIF and Notch-2 by IL-1beta/TGF-beta can be reverted after cytokine withdrawal. Remarkably, however, up-regulated Bmi-1 levels remained unchanged after cytokine withdrawal; and the cytokine-withdrawn cells maintained strong clonogenicity, suggesting that Bmi-1 may play a crucial role in tumorigenesis. Conclusions: Our finding indicates that glioma cells without self-renewal capability in standard conditions could also contribute to glioma malignancy when cytokines, such as IL-1beta and TGF-beta, are present in the tumor environment. Targeting GSC-promoting cytokines that are highly expressed in glioblastomas may contribute to the development of more effective glioma therapies

Cell-delivered magnetic nanoparticles caused hyperthermia-mediated increased survival in a murine pancreatic cancer model

Using magnetic nanoparticles to absorb alternating magnetic field energy as a method of generating localized hyperthermia has been shown to be a potential cancer treatment. This report demonstrates a system that uses tumor homing cells to actively carry iron/iron oxide nanoparticles into tumor tissue for alternating magnetic field treatment. Paramagnetic iron/iron oxide nanoparticles were synthesized and loaded into RAW264.7 cells (mouse monocyte/macrophage-like cells), which have been shown to be tumor homing cells. A murine model of disseminated peritoneal pancreatic cancer was then generated by intraperitoneal injection of Pan02 cells. After tumor development, monocyte/macrophage-like cells loaded with iron/iron oxide nanoparticles were injected intraperitoneally and allowed to migrate into the tumor. Three days after injection, mice were exposed to an alternating magnetic field for 20 minutes to cause the cell-delivered nanoparticles to generate heat. This treatment regimen was repeated three times. A survival study demonstrated that this system can significantly increase survival in a murine pancreatic cancer model, with an average post-tumor insertion life expectancy increase of 31%. This system has the potential to become a useful method for specifically and actively delivering nanoparticles for local hyperthermia treatment of cancer

Magnetic-Fe/Fe3O4-nanoparticle-bound SN38 as carboxylesterase-cleavable prodrug for the delivery to tumors within monocytes/macrophages

The targeted delivery of therapeutics to the tumor site is highly desirable in cancer treatment, because it is capable of minimizing collateral damage. Herein, we report the synthesis of a nanoplatform, which is composed of a 15 ± 1 nm diameter core/shell Fe/Fe[subscript]3O[subscript]4 magnetic nanoparticles (MNPs) and the topoisomerase I blocker SN38 bound to the surface of the MNPs via a carboxylesterase cleavable linker. This nanoplatform demonstrated high heating ability (SAR = 522 ± 40 W/g) in an AC-magnetic field. For the purpose of targeted delivery, this nanoplatform was loaded into tumor-homing double-stable RAW264.7 cells (mouse monocyte/macrophage-like cells (Mo/Ma)), which have been engineered to express intracellular carboxylesterase (InCE) upon addition of doxycycline by a Tet-On Advanced system. The nanoplatform was taken up efficiently by these tumor-homing cells. They showed low toxicity even at high nanoplatform concentration. SN38 was released successfully by switching on the Tet-On Advanced system. We have demonstrated that this nanoplatform can be potentially used for thermochemotherapy. We will be able to achieve the following goals: (1) Specifically deliver the SN38 prodrug and magnetic nanoparticles to the cancer site as the payload of tumor-homing double-stable RAW264.7 cells; (2) Release of chemotherapeutic SN38 at the cancer site by means of the self-containing Tet-On Advanced system; (3) Provide localized magnetic hyperthermia to enhance the cancer treatment, both by killing cancer cells through magnetic heating and by activating the immune system