Xiaoshu Dai - Academia.edu (original) (raw)

Papers by Xiaoshu Dai

Journal of Clinical Oncology, Jan 20, 2021

477 Background: Napabucasin is an orally-administered NAD(P)H quinone dehydrogenase 1–bioactivata... more 477 Background: Napabucasin is an orally-administered NAD(P)H quinone dehydrogenase 1–bioactivatable investigational agent hypothesized to affect multiple oncogenic cellular pathways including STAT3. Methods: Food effects on napabucasin pharmacokinetics were evaluated in two studies: one at two sites in Japan (Study 1; JapicCTI-205447) and the other at two sites in the US and three in Canada (Study 2; NCT01775423). Study 1 enrolled healthy Japanese male volunteers (HJMV) who received napabucasin 480 mg (formula 2) per sequential design — fasting on Day (D) 1 followed by a Japanese diet (JD) on D8 — with a 6-D intervening washout. In Study 2, patients (pts) with advanced malignancies received napabucasin 500 mg (formula 1) on D1 in the fasted state, then napabucasin 500 mg (formula 2) on D4 and D8 with a high-fat breakfast [HFB] or in the fasted state per the randomized sequence per crossover design. Results: In Study 1, mean plasma napabucasin levels 6–10 h after napabucasin 480 mg administration were higher in fed (JD) vs fasted states; in the fed state, Cmax increased by 15% and AUClast by ~60% (Table), while tmax decreased by ~1.4 hours. Adverse events (AEs) in Study 1 occurred in 5/6 (83.3%) HJMVs (fasted, n=3; fed, n=5; all grade [gr] 1). In Study 2, mean concentration profiles were comparable in fasted and fed (HFB) states for napabucasin 500 mg. When comparing fasted and fed states, Cmax increased by 21% and AUClast by 39% in the fed state (Table). Interpatient variability was high: geometric CV% for CL/F was 75.9% (fed) and 141% (fasted). AEs in Study 2 occurred in 68% (17/25) of fasted pts (gr 1: n=7; gr 2: n=8; gr 3, n=2) and 50% (7/14) of pts fed an HFB (gr 1: n=2; gr 2: n=3; gr 3, n=2). Conclusions: In HJMVs, napabucasin 480 mg administered with a JD increased exposure (Cmax; AUClast; AUCinf) and decreased tmax vs the fasted state. In pts with advanced malignancies, napabucasin 500 mg administered with an HFB increased exposure (Cmax; AUClast) vs the fasted state. These exposure increases are not considered to be of clinical relevance. Clinical trial information: JapicCTI-205447; NCT01775423. [Table: see text]

Hydroxyapatite (HA) is the principal inorganic phase in bone. Synthetic hydroxyapatite particles,... more Hydroxyapatite (HA) is the principal inorganic phase in bone. Synthetic hydroxyapatite particles, films, coatings, fibers and porous skeletons are used extensively in various biomedical applications. In this contribution, sol-gel processing and electrospinning have been used to develop a technique to produce fibrous structures. Poly(vinyl alcohol) (PVA) with an average molecular weight (M W) between 40,500 g/mol and 155,000 g/mol was electrospun with a calcium phosphate based sol. The sol was prepared by reacting triethyl phosphite and calcium nitrate and was directly added to an aqueous solution of PVA. This mixture was electrospun at a voltage of 20-30 kV. The results indicate that the sol particles were distributed uniformly within the PVA fibers. This electrospun structure was calcined at 600 o C for 6 hr to obtain a residual inorganic, sub-micron fibrous network. The fibrous structure after electrospinning is retained after calcination. A variety of structures including solid fibers, micro-porous fibers and interconnected networks could be obtained after calcination. A bead-on-string structure was obtained after electrospinning for M W = 40,500 g/mol. X-Ray diffraction of this fibrous structure indicated that it consisted predominantly of hydroxyapatite with an average crystal size of almost 10-30 nm. The final morphologies of the ceramic fibers were found to depend on polymer molecular weight and sol volume fraction. Average fiber diameters were on the order of 200 nm and 800 nm for molecular weight of 67,500 g/mol and 155,000 g/mol, respectively. By judiciously controlling these material and process variables, non-woven mats of sub-micron fibers with varying degrees of interconnectivity and porosity have been produced. Such novel structures can be useful in drug delivery, tissue engineering and related biomedical applications.

Journal of Veterinary Pharmacology and Therapeutics, Oct 1, 2007

Ivermectin (IVM), a macrocyclic lactone endectocide, is widely used for the treatment and prevent... more Ivermectin (IVM), a macrocyclic lactone endectocide, is widely used for the treatment and prevention of nematode and arthropod parasites (Geary, 2005). There are many preparations of IVM commercially used worldwide, such as injectable formulations, premxes, tablets, oral pastes, oral solutions and pour-on formulations (Hu et al., 2000). During treatment, animals, such as sheep, continue to ingest parasite larvae and eggs from the contaminated environment or from infested animals. To reduce the risk of reinfestation, in practice, a second administration several days later may be required to eliminate all the parasites (Campbell, 1989; Bates, 1993). This is inconvenient and expensive in labor and drugs. To solve these problems, developing a long-acting preparation seemed to be a favorable approach, although it may have a negative impact on refugia and may cause resistance. Using a long-acting formulation would enhance parasite control in rotationally grazed pastures and also help to eliminate residual parasites from the pastures (Stromberg & Averbeck, 1999). Some long-acting formulations of IVM, such as a sustainedrelease bolus (IVOMEC Ò SR BOLUS, Merial Ltd, Atlanta, GA, USA), a controlled-release capsule (NUMECTIN 100, Merial Ltd, NSW, Australia; IVOMEC Ò MAXIMIZER TM , Merial Ltd), and a long-acting injection (IVOMEC Ò GOLD, Merial Ltd, Buenos Aires, Argentina) are commercially available. Although the sustainedrelease bolus and the controlled-release capsule achieve a considerable long-acting time for drugs, they are not easy to operate and some metal boluses stay in the rumen and damage machinery during the slaughtering process. The reported injectable long-acting formulations do not have these disadvantages, but they are nonaqueous. Compared with water, there are costly.

Advanced Materials, Dec 15, 2011

Materials Science and Engineering: C, Apr 1, 2008

ABSTRACT A polymer–inorganic sol mixture has been used to develop interconnected and highly porou... more ABSTRACT A polymer–inorganic sol mixture has been used to develop interconnected and highly porous calcium phosphate networks. The inorganic sol was developed by reacting triethyl phosphite and calcium nitrate. The sol was directly added to an aqueous solution of PVA with molecular weights between 40,500 and 155,000 g/mol. This mixture was electrospun at a voltage of 20 kV to produce fibers, whose diameter was less than 1 μm. This electrospun structure was calcined at 600 °C obtain to a highly interconnected sub-micron fibrous network (fiber size ∼ 200 nm) of calcium phosphate. The crystal size is on the order of 30 nm. Micropores could be introduced in each of the fibers by controlling the polymer molecular weight and the sol volume fraction. Such structures can have many potential uses in the repair and treatment of bone defects and in drug delivery.

Journal of the American Ceramic Society, May 1, 2007

A precursor solution containing poly(vinyl alcohol) and a calcium phosphate sol is used to produc... more A precursor solution containing poly(vinyl alcohol) and a calcium phosphate sol is used to produce fibers of hydroxyapatite. The mixture is electrospun at a voltage of 20 kV and the resultant structure is calcined at 6001C for 6 h. Experiments were conducted for polymer molecular weight (M W) between 9500 and 155 000 g/mol and sol volume fractions (V S) between 0% and 83%. The results indicate that the electrospun fiber diameter can be correlated to the solution viscosity. The polymer molecular weight and sol volume fraction have a significant effect on the ceramic structure. Highly interconnected solid or porous hydroxyapatite fibers with diameters between 200 and 500 nm and crystal sizes between 30 and 50 nm can be produced by controlling M W and V S .

Acta Biomaterialia, May 1, 2011

A series of poly(ethylene glycol)-co-poly(lactide) diacrylate macromers was synthesized with vari... more A series of poly(ethylene glycol)-co-poly(lactide) diacrylate macromers was synthesized with variable PEG molecular weights (10 or 20 kDa) and lactate contents (0 or 6 lactates per end group). These macromers were polymerized to form hydrogels by free radical polymerization using either redox or photochemical initiators. The extent of polymerization was determined by monitoring the compressive modulus of the resulting hydrogels and by quantitative determination of unreacted acrylate after exhaustive hydrolysis of the gel. Polymerization efficiency was found to depend on the lactate content of the macromer, with higher lactate macromers giving more efficient polymerization. For redox-initiated polymerization using ferrous gluconate/t-butyl hydroperoxide initiator, macromers containing approximately six lactate repeats per end group required lower concentrations of initiator to reach high conversion than lactate-free macromers. Photochemical polymerization with α,α-dimethoxy-α-phenylacetophenone (Irgacure 651(®)) was found to be less efficient than redox polymerization, requiring the addition of N-vinyl-2- pyrrolidone (NVP) as a co-monomer to achieve conversions comparable with redox polymerization. When conditions were optimized to provide near complete conversion for all gels, the presence of lactate repeat units in the hydrogel was generally found to reduce swelling and increase the compressive modulus. Calculated values of molecular weight between cross-links (M(c)) and mesh size using Flory-Rehner theory showed that macromer molecular weight had the greatest impact on the network structure of the gel.

Materials Letters, May 1, 2007

Polyvinyl alcohol (PVA) with an average molecular weight between 40,500 and 155,000 g/mol was ele... more Polyvinyl alcohol (PVA) with an average molecular weight between 40,500 and 155,000 g/mol was electrospun with a calcium phosphate based sol. The sol was prepared by reacting triethyl phosphite and calcium nitrate and was directly added to an aqueous solution of PVA. This mixture was electrospun at a voltage of 20 kV. The results indicate that the sol was distributed uniformly in

Ceramic engineering and science proceedings, Jan 20, 2010

ABSTRACT Fibers and highly porous architectures of hydroxyapatite were produced by controlled deg... more ABSTRACT Fibers and highly porous architectures of hydroxyapatite were produced by controlled degradation of a scaffold of an electrospun precursor. The precursor was prepared by aging triethyl phosphite and calcium nitrate and was directly added to an aqueous solution of Polyvinyl alcohol (PVA). This electrospun structure was calcined at various temperatures to obtain a residual inorganic network, which consisted predominantly of hydroxyapatite. The effects of process temperature and time are investigated. These structures can have many potential uses in the repair and treatment of bone defects, drug delivery and tissue engineering.

Langmuir, Jan 27, 2012

In this paper, we describe an electric-fieldassisted gel transferring technique for patterning on... more In this paper, we describe an electric-fieldassisted gel transferring technique for patterning on two-and three-dimensional media. The transfer process starts with the preparation of a block of agarose gel doped with charged nanoparticles or molecules on top of a screen mask with desired patterns. This gel/mask construct is then brought into contact with the appropriate receiving medium, such as a polymer membrane or a piece of flat hydrogel. An electric field is applied to transfer the doped charged nanoparticles or molecules into the receiving medium with a pattern defined by the screen mask. This printing method is rapid and convenient, the results are reproducible, and the process can be done without using expensive micro/nanofabrication facilities. The capability to pattern structures such as arrays of nanoparticles into three-dimensional hydrogels may find applications for positioning cell signaling molecules to control cell growth and migration.

Nanotechnology, Nov 21, 2011

This paper describes an efficient and versatile method for the fabrication of nanostructured subs... more This paper describes an efficient and versatile method for the fabrication of nanostructured substrates from a piece of tendon which comprises aligned collagen nanofibers. We used a microtome to generate the tendon slices (10-50 µm thick), which were used as a scaffold for guiding directional cell growth. Highly aligned and uniform monolayer cells sheets were obtained. The tendon slices were used as a master, and the nanostructures outlined by the bundles of collagen nanofibers were successfully transferred onto a polystyrene film using standard soft lithography. The cell growing on the nanostructured polystyrene substrate showed good adhesion and alignment. The technique developed here enables one to fabricate nanostructured substrates without using any traditional micro/nanofabrication tools. The nanostructured substrate, e.g. a slice of tendon, has excellent biocompatibility and relatively good mechanical stability, which makes this technique useful in constructing complicated 3D tissues.

I dedicate this thesis to my family: especially my parents, Lang Dai and Shangqing Wang for their... more I dedicate this thesis to my family: especially my parents, Lang Dai and Shangqing Wang for their love, support, and confidence in me through these years. They have my unconditional gratitude for their influence of my pursuit of graduate education and for being my inspiration and motivation of my life. I love them very much and can never thank them enough for all the opportunities they have given me. My sincere appreciation goes to my advisor, Professor. Satya Shivkumar, for taking me as his graduate student, introducing and guiding me through the world of electrospinning. I would like to thank Professor Richard D. Sisson for being a great mentor during my graduate study. I would also like to thank Dr. Arthur J. Coury and Dr. Thomas H. Jozefiak for giving me an opportunity and experience of working in the industry. They are the true chemists: enthusiastic, creative, and inspirational. It was such a great honor to have these great scientists as my committee members. Their wide knowledge has provided a great basis for the present thesis. Their guidance and encouragement accompanied me during every step through the thesis work. And last, but not least, my boyfriend, Anton Gurov, for all his love and support.

RNAi (RNA interference) technology has the potential to target any genes causing disease, includi... more RNAi (RNA interference) technology has the potential to target any genes causing disease, including conventionally “undruggable” targets in cancer. We previously discovered aiRNA (asymmetric interfering RNA), a next generation of gene-silencing technology with improved gene silencing efficiency and reduced off-target effects in comparison with siRNA. We have recently developed a nanoscale formulation that encapsulates therapeutic aiRNAs targeting CTNNB1 and PD-L1, named BBI-801. Here we investigate the in vivo delivery and antitumor activity of BBI-801 encapsulating aiRNAs targeting CTNNB1 and PD-L1. CTNNB1 encodes undruggable β-catenin which is a cancer stemness gene that is broadly implicated in multiple cancer types PD-L1 gene encodes a key immune checkpoint factor that mediates cancer immune evasion. In our in vivo studies, we have achieved prolong silencing of β-Catenin/PD-L1 mRNA and protein in a dose-dependent manner in a wide variety of murine tumor models, including subcutaneous human tumor xenografts, orthotopic human liver and lung tumors, as well as syngeneic mouse colorectal, breast and lung tumors. Our biodistribution analysis of fluorescence-labeled aiRNA demonstrated that the delivery of BBI-801 to xenograft tumors happens within 5 minutes of aiRNA administration and lasts at least 8 hours. In all the models we examined, significant tumor growth inhibition by BBI-801 was achieved not only in β-Catenin over-expressed colorectal tumor models, SW480 and APCmin, but also in the rest of β-Catenin normal-expressed tumor models. Finally, BBI-801 is well tolerated and no signs of toxicity were observed after repeated dosing. These exciting data support further investigation of the anti-tumor potential of BBI-801 as an anticancer therapeutic in variety of tumor indications. Citation Format: Youzhi Li, Yuan Gao, Yuxin Wang, Jie Su, Eric Hsu, Ewa Wybieralska, Janet Huang, Keyur Gada, Jun Oishi, Xiaoshu Dai, Erina Koga, Wei Li, Xiangao Sun, Emily Brooks, Chiang J. Li. In vivo delivery of asymmetric gene-silencing RNAs targeting CTNNB1 and PD-L1 show a broad spectrum of potent antitumor activities in preclinical cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-069. doi:10.1158/1538-7445.AM2017-LB-069

Introduction: Napabucasin is an NQO1-bioactivatable investigational agent hypothesized to affect ... more Introduction: Napabucasin is an NQO1-bioactivatable investigational agent hypothesized to affect multiple oncogenic cellular pathways including pSTAT3 through the generation of reactive oxygen species. The primary objectives of this phase 1, open-label study in healthy male subjects were to characterize the absorption, metabolism, and excretion of 14C-napabucasin and to determine the pharmacokinetics of 14C-napabucasin and relevant metabolites in plasma, urine, and feces. The secondary objective was to assess safety and tolerability of napabucasin. Methods: Healthy male adult (age 18–45 years) subjects were eligible to receive a single oral 240-mg dose of napabucasin containing ~100 μCi of 14C-napabucasin. Blood, urine, and feces were collected up to 264 hours (h; 11 days) postdose. Whole blood, plasma, urine, fecal, and expired air samples were assayed for total radioactivity (TR). Plasma, urine, and fecal samples were assayed for napabucasin and metabolites. Results: Overall, 8 subjects (mean [range] age 29 [23–39] years) were enrolled. The mean TR recovered was 81.1%. In general, elimination of 14C-napabucasin was predominantly via feces (57.2%), to a lesser extent via urine (23.8%), and was negligible in expired air. Most (76.0%) recovery was within 48 h postdose. 14C-napabucasin was rapidly absorbed (median time to peak concentration 2.8 h) and underwent extensive reductive metabolism to yield dihydro-napabucasin (M1), the sole major circulating metabolite. Systemic exposure to 14C-napabucasin was higher than M1, and M1 plasma concentration versus time profiles generally mirrored 14C-napabucasin. Similar arithmetic mean half-lives for 14C-napabuscasin and M1 (7.9 h and 7.1 h, respectively) suggest that the rate of formation of the reduced metabolite is rate limiting. The TR whole blood:plasma ratio of 0.4 indicated that circulating drug-related compounds were essentially confined to plasma. Four minor metabolites were identified but accounted for ≤7.0% of TR in plasma. Consistent with preclinical animal models, no uniquely human or disproportionate metabolite was quantified. Secondary glucuronide and sulfate conjugates were common urinary metabolites. These data suggest that 14C-napabucasin was mainly cleared by reductive metabolism and, to a lesser extent, by renal elimination. 14C-napabucasin and M1 recovered in urine accounted for 13.2% and 9.6% of the administered dose, respectively. Apparent renal clearance of 14C-napabucasin and M1 were 8.1 L/h and 7.9 L/h, respectively. All subjects experienced treatment-emergent adverse events (TEAEs). All TEAEs were mild (grade 1) and the majority were assessed as related to napabucasin. The most commonly reported TEAEs were gastrointestinal disorders and, of these, diarrhea was reported most frequently and generally started within 4.5–5.0 h postdose and resolved without treatment. There were no clinically significant laboratory, vital sign, electrocardiogram, or physical examination changes. Conclusions: 14C-napabucasin is primarily excreted through feces. 14C-napabucasin underwent extensive metabolism to yield M1 as the sole major circulating metabolite. No uniquely human or disproportionate metabolite was quantified. A single oral 240-mg dose of napabucasin was tolerated in healthy male subjects. Citation Format: Xiaoshu Dai, Michael D Karol, Matthew Hitron, Marjie Hard, J Evan Blanchard, Nicola Eraut, Natalie Rich, Brandon Gufford. Mass balance and pharmacokinetics of an oral dose of 14C-napabucasin in healthy adult male subjects [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A113. doi:10.1158/1535-7163.TARG-19-A113

The protein K-Ras is a molecular switch that under normal conditions regulates cell growth and ce... more The protein K-Ras is a molecular switch that under normal conditions regulates cell growth and cell division. Mutations in this protein lead to the formation of tumors through continuous cell growth. About 30% of human cancers have a mutated Ras protein that is constitutively bound to GTP due to decreased GTPase activity and insensitivity to GAP action. Ras is also an important factor in many cancers in which it is not mutated but rather functionally activated through inappropriate activity of other signal transduction elements. Mutated K-Ras proteins are found in a large proportion of all tumour cells. K-Ras protein occupies a central position of interest. The identification of oncogenically mutated K-Ras in many human cancers led to major efforts to target this constitutively activated protein as a rational and selective treatment. Despite decades of active agent research, significant challenges still remain to develop therapeutic inhibitors of K-Ras. To elucidate the function of K-Ras in the cancer development and maintenance, we developed asymmetric interfering RNAs (aiRNAs) which are able to silence target genes with high potency leading to long-lasting knockdown, and reducing off-target effects, and investigated the dependency of K-ras on cell survival in several types of human cancer cell lines. Much to our surprise, we found K-Ras plays a more significant role for gastric cancer maintenance compared to other types of cancer. Here we report aiRNA-induced silencing of K-Ras inhibited the cell proliferation of gastric cancer cells and the ability of gastric cancer cells to form colonies compared to other cancer types. Accumulating evidence has revealed that cancer stem cells (CSCs) are highly associated with prognosis, metastasis, and recurrence. To investigate the effect of K-Ras on CSCs, we tested the K-Ras gene silencing effects on an in vitro CSC culturing system. As a result, K-Ras inhibition decreased the colonies derived from gastric CSCs and altered the gene expression patterns of several genes involved in “stemness” compared to other cancer types. The results of these studies suggest that gastric cancer and gastric CSCs are affected by the K-Ras oncogene and that Kras aiRNAs are promising therapeutic candidates for the treatment of gastric cancer. Citation Format: Xiangao Sun, Youzhi Li, Hiroki Umehara, Jun Oishi, Nithya Jesuraj, Jelena Barbulovic, Xiaoshu Dai, Keyur Gada, Chiang Li. Specific and potent silencing of K-Ras by asymmetric RNA technology reveals addiction of gastric cancer stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-47. doi:10.1158/1538-7445.AM2014-LB-47

Journal of Clinical Oncology, May 20, 2018

4110Background: NAPA is an oral investigational agent, hypothesized to inhibit cancer stemness pa... more 4110Background: NAPA is an oral investigational agent, hypothesized to inhibit cancer stemness pathways, including STAT3 pathway implicated in cancer stem-cell viability. We report updated data in ...

ABSTRACT To simulate the quenching process the surface heat transfer coefficient as a function of... more ABSTRACT To simulate the quenching process the surface heat transfer coefficient as a function of temperature plays the critical role in predicting temperature evolution accurately inside a quenched part. In this study, an Inconel and SAE4140 steel quench probes are used to investigate the effect of quench start temperature on the heat transfer process and the subsequent surface heat transfer coefficient. The results show that the heat transfer coefficient not only depends on the part surface temperature, but also on the initial temperature of the quenched part. It was also determined that the decrease in quench start temperature shifts the temperature for maximum heat transfer coefficient to lower temperatures.

PVA with an average molecular weight between 50,000 and 124,000 g/mol was electrospun with a Calc... more PVA with an average molecular weight between 50,000 and 124,000 g/mol was electrospun with a Calcium Phosphate based sol. The sol was prepared by reacting Triethyl Phosphite and Calcium Nitrate and was directly added to an aqueous solution of PVA. This mixture was electrospun at a voltage of 20-30 kV. The results indicate that the sol was distributed uniformly in the PVA fibers, whose diameter was on the order of 2 µm. This electrospun structure was calcined at 600 o C for 6 hr to obtain a residual inorganic, sub-micron fibrous network. X-ray diffraction of this fibrous structure indicated that it consisted predominantly of hydroxyapatite with an average crystal size of almost 30 nm. Dense or micro-porous hydroxyapatite fibers and scaffolds could be obtained by varying the polymer molecular weight and the polymer/sol ratio. The micro-porous fibers can have many potential uses in the repair and treatment of bone defects, drug delivery and tissue engineering.

A series of poly(ethylene glycol)-co-poly(lactate) diacrylate macromers was synthesized with vari... more A series of poly(ethylene glycol)-co-poly(lactate) diacrylate macromers was synthesized with variable PEG molecular weight (10 and 20 kDa) and lactate content (0-6 lactate per endgroup). These macromers were polymerized to form hydrogels by free radical polymerization using either redox or photochemical initiators. The extent of polymerization was monitored by compressive modulus of the resulting hydrogels and a quantitative determination of unreacted acrylate after exhaustive hydrolysis of the gel. Polymerization efficiency was found to depend on the lactate content of the macromer, with higher lactate macromers giving more efficient polymerization. For redox-initiated polymerization using ferrous gluconate/t-butyl hydroperoxide initiator, macromers containing approximately six lactate repeats per endgroup required lower concentrations of initiator to reach high conversion than lactate-free macromers. Photochemical polymerization with α, α-dimethoxy-α-phenylacetophenone (Irgacure 6...