Immune Mechanisms Regulating Pharmacokinetics and Pharmacodynamics of PEGylated Liposomal Anticancer Agents

Nanotechnology has made significant advances in drug delivery system for the treatment of cancer. Among various nanoparticle (NP) platforms, liposomes have been most widely used as a NP drug carrier for cancer therapy. High variation in pharmacokinetics (PK) and pharmacodynamics (PD) of liposome-based therapeutics has been reported. However, the interaction of liposome-based therapeutics with the immune system, specifically the mononuclear phagocyte system (MPS), and underlying molecular mechanisms for variable responses to liposomal drugs remain poorly understood. The objective of this dissertation was to elucidate immune mechanisms for the variable responses to PEGylated liposomal doxorubicin (PLD; Doxil®), a clinically relevant NP, in animal models and in patients. In vitro, in vivo and clinical systems were investigated to evaluate the effects of chemokines (CCL2 and CCL5), heterogeneity of the tumor microenvironment, and genetic variations on PK and PD of PLD. Results showed that there was a significantly positive linear relationship between PLD exposure (AUC) and total amount of CCL2 and CCL5, most prevalent chemokines in plasma, in patients with recurrent ovarian cancer. Consistent with these findings, preclinical studies using mice bearing SKOV3 orthotopic ovarian cancer xenografts demonstrated that PLD induced the production and secretion of chemokines into plasma. In addition, in vitro studies using human monocytic THP-1 cells demonstrated that PLD altered monocyte migration towards CCL2 and CCL5. The PK and efficacy studies of PLD in murine models of breast cancer showed that heterogeneous tumor microenvironment was associated with significantly different tumor delivery and efficacy of PLD, but not small molecule doxorubicin between two breast tumor models. A candidate genetic locus that was associated with clearance of PLD in 23 inbred mouse strains contains a gene that encodes for engulfment adapter PTB domain containing 1 (Gulp1). By using integrated approaches, we were able to identify the immunological mechanisms at the molecular, tissue, and clinical levels that may contribute to inter-individual variability in PK and PD of PLD. This dissertation research has a potential to make an impact on development of future NP-based anticancer therapeutics as well as on clinical use of PLD (Doxil®) and other PEGylated liposomal anticancer agents.Doctor of Philosoph

Exploiting Multiple Embeddings for Chinese Named Entity Recognition

Identifying the named entities mentioned in text would enrich many semantic applications at the downstream level. However, due to the predominant usage of colloquial language in microblogs, the named entity recognition (NER) in Chinese microblogs experience significant performance deterioration, compared with performing NER in formal Chinese corpus. In this paper, we propose a simple yet effective neural framework to derive the character-level embeddings for NER in Chinese text, named ME-CNER. A character embedding is derived with rich semantic information harnessed at multiple granularities, ranging from radical, character to word levels. The experimental results demonstrate that the proposed approach achieves a large performance improvement on Weibo dataset and comparable performance on MSRA news dataset with lower computational cost against the existing state-of-the-art alternatives.Comment: accepted at CIKM 201

The effects of nanoparticle drug loading on the pharmacokinetics of anticancer agents

Major advances in carrier-mediated agents, which include nanoparticles, nanosomes and conjugates, have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages, such as greater solubility, duration of exposure and delivery to the site of action over their small-molecule counterparts, there is substantial variability in systemic clearance and distribution, tumor delivery and pharmacologic effects (efficacy and toxicity) of these agents. This review provides an overview of factors that affect the pharmacokinetics and pharmacodynamics of carrier-mediated agents in preclinical models and patients

Visual Psychophysics and Physiological Optics Handheld Shape Discrimination Hyperacuity Test on a Mobile Device for Remote Monitoring of Visual Function in Maculopathy

PURPOSE. Frequency monitoring of age-related macular degeneration (AMD) and diabetic retinopathy (DR) is crucial for timely intervention. This study evaluated a handheld shape discrimination hyperacuity (hSDH) test iPhone app designed for visual function selfmonitoring in patients with AMD and DR. METHODS. One hundred subjects (27 visually normal, 37 with AMD, and 36 with DR) were included based on clinical documentation and visual acuity of 20/100 or better. The hSDH test was implemented on the iOS platform. A cross-sectional study was conducted to compare the hSDH test with a previously established desktop SDH (dSDH) test and to assess the effect of disease severity on the hSDH test. A user survey was also conducted to assess the usability of the hSDH test on the mobile device. RESULTS. The hSDH test and dSDH test were highly correlated (r ¼ 0.88, P < 0.0001). BlandAltman analysis indicated no significant difference in hSDH and dSDH measurements. Oneway ANOVA indicated that the mean hSDH measurement of the eyes with advanced AMD (n ¼ 16) or with severe to very severe nonproliferative DR (NPDR) (n ¼ 12) was significantly worse than that of the eyes with intermediate AMD (n ¼ 11) or with mild to moderate NPDR (n ¼ 11) (P < 0.0001). Ninety-eight percent of 46 patients (10 with AMD and 36 with DR) who completed the usability survey reported that the hSDH test was easy to use. CONCLUSIONS. This study demonstrated that the hSDH test on a mobile device is comparable to PC-based testing methods. As a mobile app, it is intuitive to use, readily accessible, and sensitive to the severity of maculopathy. It has the potential to provide patients having maculopathy with a new tool to monitor their vision at home

Towards single particle imaging of human chromosomes at SACLA

Robinson I., Schwenke J., Yusuf M., et al. Towards single particle imaging of human chromosomes at SACLA. Journal of Physics B: Atomic, Molecular and Optical Physics, 48, 24, 244007. https://doi.org/10.1088/0953-4075/48/24/244007

FAM120A couples SREBP-dependent transcription and splicing of lipogenesis enzymes downstream of mTORC1

The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that stimulates macromolecule synthesis through transcription, RNA processing, and post-translational modification of metabolic enzymes. However, the mechanisms of how mTORC1 orchestrates multiple steps of gene expression programs remain unclear. Here, we identify family with sequence similarity 120A (FAM120A) as a transcription co-activator that couples transcription and splicing of de novo lipid synthesis enzymes downstream of mTORC1-serine/arginine-rich protein kinase 2 (SRPK2) signaling. The mTORC1-activated SRPK2 phosphorylates splicing factor serine/arginine-rich splicing factor 1 (SRSF1), enhancing its binding to FAM120A. FAM120A directly interacts with a lipogenic transcription factor SREBP1 at active promoters, thereby bridging the newly transcribed lipogenic genes from RNA polymerase II to the SRSF1 and U1-70K-containing RNA-splicing machinery. This mTORC1-regulated, multi-protein complex promotes efficient splicing and stability of lipogenic transcripts, resulting in fatty acid synthesis and cancer cell proliferation. These results elucidate FAM120A as a critical transcription co-factor that connects mTORC1-dependent gene regulation programs for anabolic cell growth

Biological, clinical and population relevance of 95 loci for blood lipids.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD