Delivery Of High Levels Research Articles

DNAzyme-Mediated Cascade Nanoreactor for Cuproptosis-Promoted Pancreatic Cancer Synergistic Therapy.

Cuproptosis, a kind of newly recognized cell death modality, shows enormous prospect in cancer treatment. The inducer of cuproptosis has more advantages in tumor therapy, especially that can trigger cuproptosis and chemodynamic therapy (CDT) simultaneously. However, cuproptosis is restricted to the deficiency of intracellular copper ions and the nonspecific delivery of copper-based ionophores. Therefore, high level delivery, responsive release, and utilizing synergistic-function of inducer become the key on cuproptosis-based oncotherapy. In this work, a cascade nanosystem is constructed for enhanced cuproptosis and CDT. In the weak acidic environment of tumor cells, DNA, zinc ions, and Cu+ can release from the nanosystem. Since Cu+ having superior performance in mediating both Fenton-like reaction and cuproptosis, the released Cu+ induces cuproptosis and CDT efficiently, accompanied by Cu2+ generation. Then Cu2+ can be converted into Cu+ partially by glutathione (GSH) to from a Cu+ supply loop and ensure the synergistic action. Meanwhile, the consumption of GSH also contributes to cuproptosis and CDT in return. Finally, DNA and Zn2+ form DNAzyme to shear catalase-related RNA, resulting in the accumulation of hydrogen peroxide and further enhancing combination therapy. These results provide a promising nanotherapeutic platform and may inspire the design for potential cancer treatment based on cuproptosis.

High concentrations of membrane-fed ivermectin are required for substantial lethal and sublethal impacts on Aedes aegypti

BackgroundWith widespread insecticide resistance in mosquito vectors, there is a pressing need to evaluate alternatives with different modes of action. Blood containing the antihelminthic drug ivermectin has been shown to have lethal and sub-lethal effects on mosquitoes. Almost all work to date has been on Anopheles spp., but impacts on other anthropophagic vectors could provide new options for their control, or additional value to anti-malarial ivermectin programmes.MethodsUsing dose-response assays, we evaluated the effects of ivermectin delivered by membrane feeding on daily mortality (up to 14 days post-blood feed) and fecundity of an Indian strain of Aedes aegypti.ResultsThe 7-day lethal concentration of ivermectin required to kill 50% of adult mosquitoes was calculated to be 178.6 ng/ml (95% confidence intervals 142.3–218.4) for Ae. aegypti, which is much higher than that recorded for Anopheles spp. in any previous study. In addition, significant effects on fecundity and egg hatch rates were only recorded at high ivermectin concentrations (≥ 250 ng/ul).ConclusionOur results suggest that levels of ivermectin present in human blood at current dosing regimes in mass drug administration campaigns, or even those in a recent higher-dose anti-malaria trial, are unlikely to have a substantial impact on Ae. aegypti. Moreover, owing to the strong anthropophagy of Ae. aegypti, delivery of higher levels of ivermectin in livestock blood is also unlikely to be an effective option for its control. However, other potential toxic impacts of ivermectin metabolites, accumulation in tissues, sublethal effects on behaviour, or antiviral action might increase the efficacy of ivermectin against Ae. aegypti and the arboviral diseases it transmits, and require further investigation.Graphical

Dimensional Analysis of Service Quality: Small Construction Business and Australian Household

<p>The survival rate of small businesses operating in the Australian building maintenance industry (SBBM) has been decreasing due to high competition. Some researchers identify the delivery of high levels of service quality as a differential strategy that can improve small business chances of survival. The objective of this study is to examine the nature of the relationships between the quality of service delivered by SBBM and the satisfaction and repurchase intention of Australian households. Additionally, provide a dimension-specific analysis of the relationship between the quality of service delivered by SBBM and the satisfaction and repurchase intention of Australian households. In order to achieve the objectives of the study, a self-completion questionnaire measuring instrument is mailed to 667 potential participants selected using simple random sampling. The measuring instrument consists of 26 questions based on the SERVPERF model. A total of 200 complete and accurate questionnaires are returned. The relationships among the main constructs of the study are tested using correlational research design. The study concludes that customer satisfaction mediates the relationship between service quality and repurchase intention. It also concludes that SBBM can achieve high levels of service quality and repurchase intention by focusing and investing in the reliability, assurance and empathy factors of service quality. The results of this study are only applicable to the Australian residential market and may not be universally applicable, which is considered a limitation.</p>

Moments of angst

Purpose– Competitive dynamics are placing greater emphasis on customer experience, making the management of the last 100 meters of the supply chain critical to differential performance. Traditionally, supply chain design has emphasized two processes: new product development and order fulfillment. Today, a third process must be designed and managed for competitive advantage. That is, the authors need to learn to design service value systems to enhance the customer experience and promote loyalty and lifetime streams of profit. This research informs the enduring challenge that underlies the delivery of high levels of customer satisfaction by enriching theory related to the design and provision of distinctive customer experience. The paper aims to discuss these issues.Design/methodology/approach– The critical incident technique (CIT), an inductive method, is employed to explore two core dimensions of expectancy theory and to identify the phenomenological and underlying systems design factors that bring about both positive and negative customer experiences.Findings– The analysis shows that few companies use customer experience as a competitive lever. Customer service failures persist from a lack of managerial commitment and poor service-delivery process design. A holistic view of customer service that emphasizes policy, people, performance measurement, and processes emerges.Originality/value– Identifying and describing the customer-experience system as a third fundamental supply chain process is an important contribution. By linking a CIT approach with cause-and-effect analysis, the authors go beyond the frequently analyzed cognitive phenomenology to identify vital systems design issues. By enhancing the customer experience at the end of the supply chain, greater advantage for all participants in the chain emerges.

Parenteral CoQ10 Formulation (BPM31510) Significantly Improves Survival In Animal Model Of Leukemia Including The Resolution Of Paraplegia Due To Brain Metastasis

Abstract Leukemia cells exhibit alterations in intermediary metabolism similar to other cancers, wherein ATP sourcing is shunted from mitochondrial oxphos towards glycolytic preponderance (Warburg Effect) to meet oncogenic proliferative demands. A consequence of this metabolic switch is the simultaneous short-circuit of the programmed death pathways, leading to a immortalization program in cancer cells including leukemia. Delivery of high levels of CoQ10 in a lipid nanodispersion mixture (BPM31510) has been demonstrated to preferentially shift metabolic networks from glycolysis towards mitochondrial-centric oxphos and recapitulation of apoptotic pathways in various cancers in vitro and in vivo models. Given the centrality of the Bcl-2 involvement in the etiology of leukemia, this study focused on investigation of the effectiveness of BPM31510 in animal models of erythroid and myeloid leukemia. Human acute erythro-leukemia (K562) and acute myeloid leukemia (KG1) models were developed in immune-compromised mice. The mice (total n=120 for each model respectively) were randomized into four (n=30/group) treatment groups: Untreated (control); BPM31510 (75 mg/kg, once/day); chemotherapy (Adriamycin [5mg/kg; once/wk]+AraC [25mg/kg; 5 days] and BPM31510+chemotherapy. All dosing were intravenous and followed a protocol of 3wk treatment followed by 1wk rest. In both leukemia models, combination of BPM31510 with chemotherapy was associated with significant increase in survival compared to other groups. BPM31510 alone improved survival compared to chemotherapy in myeloid leukemia, not in erythroleukemia model. In a separate study, a rat (Fisher 344) chloroleukemia (MIA C51) model of CNS leukemia was developed that demonstrated paraplegia and urinary retention as a result of brain metastasis. Administration of BPM31510 (50 mg/kg/day, IP) was associated with complete resolution of limb paralysis demonstrating the ability of BPM31510 in penetrating into the CNS. Moreover, BPM31510 (50 mg/kg/day, IP) administration was associated with significant increase in survival in animals with metastasis to the lungs and liver. The data provides encouraging evidence of the potential translational use of CoQ10 containing BPM31510 in the treatment of leukemia. A Phase 1 study in relapse acute leukemia is to be started shortly. Disclosures: Narain: Berg: Employment. Akmaev:Berg: Employment. Benaim:Berg: Employment. Sarangarajan:Berg: Employment. Jimenez:Berg: Membership on an entity’s Board of Directors or advisory committees.

Abstract 2771: Development of a non-thermal plasma model for neuroblastoma treatment.

Abstract Neuroblastoma is a common extra-cranial solid tumor in children. There are several clinical categories of this disease, ranging from curable to very poor prognosis in which this cancer is treated with multi-modal therapy. We have tested a novel ablative technology, using non-thermal helium generated plasma jets, as a means to selective targeting of neuroblastoma cells. Plasma consists of partially ionized molecules, free radicals and other species. We have investigated the molecular mechanisms involved in non-thermal plasma mediated tumor cell death, as well as the differences in response between tumor and normal cells. Treatment with non-thermal plasma induced apoptosis in cancer cells, while normal cells appear to be less sensitive to the toxic effects. Levels of reactive oxygen species (ROS) such as superoxide anion and hydrogen peroxide are elevated after plasma treatment, suggesting that this may contribute to cell death. Scavengers of ROS were able to abrogate apoptosis in plasma-treated cells. Plasma therapy of tumor cells may be a novel approach to delivery of high levels of ROS, offering the ability to directly target and selectively destroy neoplastic tissue. Methods enhancing the ROS effect and/or technical delivery of the free radicals uniformly to tumor cells within a mass will be needed before this technology could be translated to ablating solid tumors in vivo. Citation Format: Priya Srinivasan, Jason A. Snyder, Alexey Shashurin, Michael Keidar, Anthony D. Sandler. Development of a non-thermal plasma model for neuroblastoma treatment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2771. doi:10.1158/1538-7445.AM2013-2771 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.