DDB and Betulinic Acid-Derivatives as Potent Chemosensitizing, Chemopreventive, and Anti-HIV Agents

The overall goals of this research are to design and synthesize novel DDB and betulinic acid derivatives to evaluate their chemosensitizing, chemopreventive, and anti-HIV activities. Structure-activity relationships (SAR) are established in order to discover novel chemical entities, and to explore the mechanism(s) of action. Dimethyl diphenyl bicarboxylate (DDB) and its analog, bicyclol, were reported to have chemosensitizing activity in several multidrug resistant cancer cell lines. In a continuing study, an easy modification was accomplished by reduction to 2,2'-bismethylhydroxy DDB followed by esterification with various acids. This synthetic route was applied to develop a series of compounds and establish SAR. SAR studies on these compounds revealed that analogs with aromatic and bulky aliphatic side chains at the 2,2'-hydroxymethyl positions effectively and significantly sensitized MDR-1 over-expressed cells to three anticancer drugs, paclitaxel (TAX), vincristine (VCR), and doxorubicin (DOX). DDB derivatives 83 and 90 were five to ten times more effective than verapamil (VRP) for TAX and VCR reversal ability. Analog 73 also showed five times greater chemosensitizing effect than VRP against DOX. The mechanism of action studies showed that DDB analogs elevate cellular concentration of DOX via inhibition of P-glycoprotein. Nineteen DDB analogs were evaluated in an in vitro short-term Epstein Barr virus early antigen (EBA-EA) activation assay. Three of the most potent compounds (83, 85 and 106) were also tested for inhibitory effects on skin tumor promotion in an in vivo two-stage mouse-skin carcinogenesis test. Compound 106 with a prenyl ether had the most significant cancer preventive activity in vitro, and it also exhibited a remarkable inhibitory effect on skin tumor promotion in an in vivo two-stage mouse-skin carcinogenesis test. Importantly, active DDB analogs displayed no cytotoxicity either in chemoreversal or cancer prevention assays, suggesting that they are good leads for further development. In chapter 5, another natural product, betulinic acid, was studied since our group has focused on modification of this molecule for years. Most researches were on the modifications of positions 3, 19 and 28. Modifications on ring A were largely under investigation. Therefore, thirteen new betulinic acid derivatives were designed, synthesized, and evaluated for anticancer, cancer prevention, or anti-HIV activity. In the cytotoxic activity evaluation, compounds 120, 123, 126, and 129 exhibited GI50 < 10 μM, and compound 120 with a 3-methyl ester and 4, 23-vinyl group was the most potent. SAR study showed that the 3-methyl ester and 4, 23-vinyl group are important for potency. A C-3 carboxylic acid modification totally abolished the activity. A carboxylic acid was better than an N-heptane acetamide at C-28. In the cancer prevention assay, compound 121 showed the strongest inhibition in EBV-EA activation, and was more potent than curcumin, even at low concentrations. The SAR trends were similar to those for anticancer activity, except that a C-3 carboxylic acid was preferred. In the anti-HIV assay, only compound 119 with an ε-lactone A-ring and 28-N heptane acetamide showed weak activity, and was identified as an entry inhibitor. However, its activity was weaker than a known entry inhibitor, A43-D, with the same C-28 side chain

Interpretations of Domain Adaptations via Layer Variational Analysis

Transfer learning is known to perform efficiently in many applications empirically, yet limited literature reports the mechanism behind the scene. This study establishes both formal derivations and heuristic analysis to formulate the theory of transfer learning in deep learning. Our framework utilizing layer variational analysis proves that the success of transfer learning can be guaranteed with corresponding data conditions. Moreover, our theoretical calculation yields intuitive interpretations towards the knowledge transfer process. Subsequently, an alternative method for network-based transfer learning is derived. The method shows an increase in efficiency and accuracy for domain adaptation. It is particularly advantageous when new domain data is sufficiently sparse during adaptation. Numerical experiments over diverse tasks validated our theory and verified that our analytic expression achieved better performance in domain adaptation than the gradient descent method.Comment: Published at ICLR 202

A Mixed-methods Study of Governance Mechanisms and Outsourcing Information System Services on Goal Performance

Background: Information systems outsourcing (ISO) is one of the critical businesses in information technology outsourcing (ITO). Due to the increasing complexity of ISO, the failure rate of such outsourcing increases. Outsourcing information system services (OISS) was thus proposed to deal with this. A conceptual framework based on the information processing view was developed to investigate how the client firms assess OISS goal performance. Governance mechanisms (governance structure, relational governance, and IT coordination) were treated as antecedents of transaction cost and outsourcing flexibility; these would further affect goal performance (goal achievement and goal exceedance) with task complexity as a moderator. Method: A mix-methods study was conducted; the qualitative approach was employed to validate the conceptual framework by interviewing three managers with experiences in OISS from the client firms, whereas the quantitative approach, with 206 responses from those with OISS experiences from the client firms, provides empirical evidence. Results: The results indicated that relational governance effectively reduced transaction cost and increased outsourcing flexibility; the governance structure was also vital for outsourcing flexibility. Transaction cost was found to negatively affect goal achievement, and outsourcing flexibility positively affected both goal achievement and goal exceedance. The moderating effects of task complexity were also confirmed. Conclusion: The results extended the information processing view to OISS and proved that transaction cost and outsourcing flexibility are necessary to link governance mechanisms and goal performance. Practically, the client firms are suggested to maintain a positive relationship with the OISS provider. The OISS provider should offer an exclusive channel during and after the execution of the OISS project to reduce the possible cost that occurs during the implementation and improve the outsourcing flexibility to allow the client firms to consider their goals have been achieved and beyond their expectations. By doing so, the effect of goal performance can be maximized

Epidermal growth factor receptor regulates β-catenin location, stability, and transcriptional activity in oral cancer

<p>Abstract</p> <p>Background</p> <p>Many cancerous cells accumulate β-catenin in the nucleus. We examined the role of epidermal growth factor receptor (EGFR) signaling in the accumulation of β-catenin in the nuclei of oral cancer cells.</p> <p>Results</p> <p>We used two strains of cultured oral cancer cells, one with reduced EGFR expression (OECM1 cells) and one with elevated EGFR expression (SAS cells), and measured downstream effects, such as phosphorylation of β-catenin and GSK-3β, association of β-catenin with E-cadherin, and target gene regulation. We also studied the expression of EGFR, β-catenin, and cyclin D1 in 112 samples of oral cancer by immunostaining. Activation of EGFR signaling increased the amount of β-catenin in the nucleus and decreased the amount in the membranes. EGF treatment increased phosphorylation of β-catenin (tyrosine) and GSK-3β(Ser-(9), resulting in a loss of β-catenin association with E-cadherin. TOP-FLASH and FOP-FLASH reporter assays demonstrated that the EGFR signal regulates β-catenin transcriptional activity and mediates cyclin D1 expression. Chromatin immunoprecipitation experiments indicated that the EGFR signal affects chromatin architecture at the regulatory element of cyclin D1, and that the CBP, HDAC1, and Suv39h1 histone/chromatin remodeling complex is involved in this process. Immunostaining showed a significant association between EGFR expression and aberrant accumulation of β-catenin in oral cancer.</p> <p>Conclusions</p> <p>EGFR signaling regulates β-catenin localization and stability, target gene expression, and tumor progression in oral cancer. Moreover, our data suggest that aberrant accumulation of β-catenin under EGFR activation is a malignancy marker of oral cancer.</p

Influence of aluminium sheet surface modification on the self-piercing riveting process and the joint static lap shear strength

Self-piercing riveting (SPR) has been widely used in automotive as one of the major joining technologies for aluminium structures due to its advantages over some of the more traditional joining technologies. Research has shown that friction is a very important factor that influences both the riveting process and the joint strength for SPR, but these influences have not been fully understood. In this paper, AA5754 sheets with different surface textures, such as original with solid wax, hot water washed, sandpaper ground and grit blasted, were used to study the influence of friction on therivet inserting process, joint features and static lap shear strength. The results of joint features and rivet setting displacement-force curve showed that hot water wash and sandpaper grinding on aluminium sheet did not have significant influence on the rivet inserting process and joint features; however, for joints with grit-blasted substrates, the rivet -setting forces were higher at the beginning, and a middle section of the curve and the joint features, such as interlocks and minimum remaining bottom material thickness (Tmin), were clearly altered. The lap shear tests showed that hot water washing can slightly increase the lap shear strength, sandpaper grinding increased the static lap shear strength further and grit blasting increased the static lap shear strength the most

Feature Spectrum Topology

Topology is a fundamental aspect of quantum physics, and it has led to key breakthroughs and results in various fields of quantum materials. In condensed matters, this has culminated in the recent discovery of symmetry-protected topological phases. However, symmetry-based topological characterizations rely heavily on symmetry analysis and are incapable of detecting the topological phases in systems where the symmetry is broken, thus missing a large portion of interesting topological physics. Here, we propose a new approach to understanding the topological nature of quantum materials, which we call feature spectrum topology. In this framework, the ground-state is separated into different partitions by the eigenspectrum of a feature, a particular chosen internal quantum degree of freedom, such as spin or pseudo-spin, and the topological properties are determined by analysis of these ground-state partitions. We show that bulk-boundary correspondence guarantees gapless spectral flows in either one of the energy or feature spectrum. Most importantly, such 'feature-energy duality' of gapless spectral flows serves as a fundamental manifestation of a topological phase, thereby paving a new way towards topological characterizations beyond symmetry considerations. Our development reveals the topological nature of a quantum ground state hidden outside symmetry-based characterizations, hence, providing a platform for a more refined search of unconventional topological materials