Biodistribution and pharmacokinetics of a telodendrimer micellar paclitaxel nanoformulation in a mouse xenograft model of ovarian cancer

Wenwu Xiao1, Juntao Luo2, Teesta Jain3, John Riggs3, Harry P Tseng1, Paul T Henderson3, Simon R Cherry4, Douglas Rowland4, Kit S Lam1,31Department of Biochemistry and Molecular Medicine, UC Davis Cancer Center, University of California Davis, Sacramento, CA; 2Department of Pharmacology, SUNY Upstate Cancer Research Institute, SUNY Upstate Medical University, Syracuse, NY; 3Department of Internal Medicine, Division of Hematology and Oncology, 4Department of Biomedical Engineering, UC Davis Cancer Center, University of California Davis, Davis, CABackground: A multifunctional telodendrimer-based micelle system was characterized for delivery of imaging and chemotherapy agents to mouse tumor xenografts. Previous optical imaging studies demonstrated qualitatively that these classes of nanoparticles, called nanomicelles, preferentially accumulate at tumor sites in mice. The research reported herein describes the detailed quantitative imaging and biodistribution profiling of nanomicelles loaded with a cargo of paclitaxel.Methods: The telodendrimer was covalently labeled with 125I and the nanomicelles were loaded with 14C-paclitaxel, which allowed measurement of pharmacokinetics and biodistribution in the mice using microSPECT/CT imaging and liquid scintillation counting, respectively.Results: The radio imaging data showed preferential accumulation of nanomicelles at the tumor site along with a slower clearance rate than paclitaxel formulated in Cremophor EL (Taxol®). Liquid scintillation counting confirmed that 14C-labeled paclitaxel sequestered in nanomicelles had increased uptake by tumor tissue and slower pharmacokinetics than Taxol.Conclusion: Overall, the results indicate that nanomicelle-formulated paclitaxel is a potentially superior formulation compared with Taxol in terms of water solubility, pharmacokinetics, and tumor accumulation, and may be clinically useful for both tumor imaging and improved chemotherapy applications.Keywords: telodendrimer, nanomicelle, paclitaxel, microSPECT/CT, imaging guided drug deliver

Towards the Formalization of Fractional Calculus in Higher-Order Logic

Fractional calculus is a generalization of classical theories of integration and differentiation to arbitrary order (i.e., real or complex numbers). In the last two decades, this new mathematical modeling approach has been widely used to analyze a wide class of physical systems in various fields of science and engineering. In this paper, we describe an ongoing project which aims at formalizing the basic theories of fractional calculus in the HOL Light theorem prover. Mainly, we present the motivation and application of such formalization efforts, a roadmap to achieve our goals, current status of the project and future milestones.Comment: 9 page

Tailoring the atomic structure of graphene nanoribbons by STM lithography

The practical realization of nano-scale electronics faces two major challenges: the precise engineering of the building blocks and their assembly into functional circuits. In spite of the exceptional electronic properties of carbon nanotubes only basic demonstration-devices have been realized by time-consuming processes. This is mainly due to the lack of selective growth and reliable assembly processes for nanotubes. However, graphene offers an attractive alternative. Here we report the patterning of graphene nanoribbons (GNRs) and bent junctions with nanometer precision, well-defined widths and predetermined crystallographic orientations allowing us to fully engineer their electronic structure using scanning tunneling microscope (STM) lithography. The atomic structure and electronic properties of the ribbons have been investigated by STM and tunneling spectroscopy measurements. Opening of confinement gaps up to 0.5 eV, allowing room temperature operation of GNR-based devices, is reported. This method avoids the difficulties of assembling nano-scale components and allows the realization of complete integrated circuits, operating as room temperature ballistic electronic devices.Comment: 8 pages text, 5 figures, Nature Nanotechnology, in pres

Activation of Cytotoxic and Regulatory Functions of NK Cells by Sindbis Viral Vectors

Oncolytic viruses (OVs) represent a relatively novel anti-cancer modality. Like other new cancer treatments, effective OV therapy will likely require combination with conventional treatments. In order to design combinatorial treatments that work well together, a greater scrutiny of the mechanisms behind the individual treatments is needed. Sindbis virus (SV) based vectors have previously been shown to target and kill tumors in xenograft, syngeneic, and spontaneous mouse models. However, the effect of SV treatment on the immune system has not yet been studied. Here we used a variety of methods, including FACS analysis, cytotoxicity assays, cell depletion, imaging of tumor growth, cytokine blockade, and survival experiments, to study how SV therapy affects Natural Killer (NK) cell function in SCID mice bearing human ovarian carcinoma tumors. Surprisingly, we found that SV anti-cancer efficacy is largely NK cell-dependent. Furthermore, the enhanced therapeutic effect previously observed from Sin/IL12 vectors, which carry the gene for interleukin 12, is also NK cell dependent, but works through a separate IFNγ-dependent mechanism, which also induces the activation of peritoneal macrophages. These results demonstrate the multimodular nature of SV therapy, and open up new possibilities for potential synergistic or additive combinatorial therapies with other treatments

Advances in ophthalmic drug delivery

Various strategies for ocular drug delivery are considered; from basic formulation techniques for improving availability of drugs; viscosity enhancers and mucoadhesives aid drug retention and penetration enhancers promote drug transport into the eye. The use of drug loaded contact lenses and ocular inserts allows drugs to be better placed where they are needed for more direct delivery. Developments in ocular implants gives a means to overcome the physical barriers that traditionally prevented effective treatment. Implant technologies are under development allowing long term drug delivery from a single procedure, these devices allow posterior chamber diseases to be effectively treated. Future developments could bring artificial corneas to eliminate the need for donor tissue and one-off implantable drug depots lasting the patient’s lifetime

Deep diversification of an AAV capsid protein by machine learning.

Modern experimental technologies can assay large numbers of biological sequences, but engineered protein libraries rarely exceed the sequence diversity of natural protein families. Machine learning (ML) models trained directly on experimental data without biophysical modeling provide one route to accessing the full potential diversity of engineered proteins. Here we apply deep learning to design highly diverse adeno-associated virus 2 (AAV2) capsid protein variants that remain viable for packaging of a DNA payload. Focusing on a 28-amino acid segment, we generated 201,426 variants of the AAV2 wild-type (WT) sequence yielding 110,689 viable engineered capsids, 57,348 of which surpass the average diversity of natural AAV serotype sequences, with 12-29 mutations across this region. Even when trained on limited data, deep neural network models accurately predict capsid viability across diverse variants. This approach unlocks vast areas of functional but previously unreachable sequence space, with many potential applications for the generation of improved viral vectors and protein therapeutics

UDP-glucuronosyltransferase UGT1A7 genetic polymorphisms in hepatocellular carcinoma: a differential impact according to seropositivity of HBV or HCV markers?

<p>Abstract</p> <p>Background:</p> <p>We conducted a case-control study to evaluate the role of UDP-glucuronosyltransferase 1A7 (UGT1A7) polymorphisms in the onset of hepatocellular carcinoma (HCC).</p> <p>Methods:</p> <p>The study included 165 patients with HCC, 134 with cirrhosis and 142 controls without liver disease, matched for age and hospital. All were men younger than 75 years. HCC and cirrhosis patients were stratified according to time since cirrhosis diagnosis.</p> <p>Results:</p> <p>We found a positive association between the UGT1A7*3/*3 genotype and HCC when the comparison was restricted to patients whose disease was of viral origin [OR = 3.4 (0.3–45)] but a negative association when it included only alcoholic patients [OR = 0.1 (0.02–0.6), p = 0.01].</p> <p>Conclusion:</p> <p>Our study shows that UGT1A7 may play a role in hepatocellular carcinogenesis and that this role may differ according to the primary cause of the cirrhosis.</p

Процесс анализа угроз, влияющих на экономическую устойчивость предприятия

На основании проведенного исследования были выявлены факторы возникновения угроз, их группировка по степени воздействию на экономическую устойчивость предприятий и рассмотрена формализация процесса анализа угроз экономической устойчивости предприятий. В условиях рыночной экономики невозможно управлять предприятием без учета влияния угроз, а для эффективного управления важно не только знать об их присутствии, а и правильно идентифицировать конкретную угрозу.На підставі проведеного дослідження були виявлені чинники виникнення загроз, їх угруповання по степені впливу на економічну стійкість підприємств і розглянута формалізація процесу аналізу загроз економічної стійкості підприємств. В умовах ринкової економіки неможливо керувати підприємством без вивчення впливу загроз, а для ефективного керування важливо не тільки знати про їх присутність, а і правильно ідентифікувати конкретну загрозу.On the basis of the conducted research the factors of origin of threats were exposed, their gourmet on a degree to influence on economic stability of enterprises and formalization of process of analysis of threats of economic stability of enterprises is considered. In the conditions of market economy it is impossible to manage an enterprise without taking into account influencing of threats, and for the effective management it is important not only to know about their presence, and to identify the concrete threat correctly