Preclinical Efficacy of Cabazitaxel Loaded Poly (2-alkyl cyanoacrylate) Nanoparticle Variants

\ua9 2024 Valsalakumari et al. This work is published and licensed by Dove Medical Press Limited.Background: Biodegradable poly(alkyl cyanoacrylate) (PACA) nanoparticles (NPs) are receiving increasing attention in anti-cancer nanomedicine development not only for targeted cancer chemotherapy, but also for modulation of the tumor microenvironment. We previously reported promising results with cabazitaxel (CBZ) loaded poly(2-ethylbutyl cyanoacrylate) NPs (PEBCA-CBZ NPs) in a patient derived xenograft (PDX) model of triple-negative breast cancer, and this was associated with a decrease in M2 macrophages. The present study aims at comparing two endotoxin-free PACA NP variants (PEBCA and poly(2-ethylhexyl cyanoacrylate); PEHCA), loaded with CBZ and test whether conjugation with folate would improve their effect. Methods: Cytotoxicity assays and cellular uptake of NPs by flow cytometry were performed in different breast cancer cells. Biodistribution and efficacy studies were performed in PDX models of breast cancer. Tumor associated immune cells were analyzed by multiparametric flow cytometry. Results: In vitro studies showed similar NP-induced cytotoxicity patterns despite difference in early NP internalization. On intravenous injection, the liver cleared the majority of NPs. Efficacy studies in the HBCx39 PDX model demonstrated an enhanced effect of drug-loaded PEBCA variants compared with free drug and PEHCA NPs. Furthermore, the folate conjugated PEBCA variant did not show any enhanced effects compared with the unconjugated counterpart which might be due to unfavorable orientation of folate on the NPs. Finally, analyses of the immune cell populations in tumors revealed that treatment with drug loaded PEBCA variants affected the myeloid cells, especially macrophages, contributing to an inflammatory, immune activated tumor microenvironment. Conclusion: We report for the first time, comparative efficacy of PEBCA and PEHCA NP variants in triple negative breast cancer models and show that CBZ-loaded PEBCA NPs exhibit a combined effect on tumor cells and on the tumor associated myeloid compartment, which may boost the anti-tumor response

Quantitative detection of 4-hydroxyequilenin–DNA adducts in mammalian cells using an immunoassay with a novel monoclonal antibody

Estrogen–DNA adducts are potential biomarkers for assessing the risk and development of estrogen-associated cancers. 4-Hydroxyequilenin (4-OHEN) and 4-hydroxyequilin (4-OHEQ), the metabolites of equine estrogens present in common hormone replacement therapy (HRT) formulations, are capable of producing bulky 4-OHEN–DNA adducts. Although the formation of 4-OHEN–DNA adducts has been reported, their quantitative detection in mammalian cells has not been done. To quantify such DNA adducts, we generated a novel monoclonal antibody (4OHEN-1) specific for 4-OHEN–DNA adducts. The primary epitope recognized is one type of stereoisomers of 4-OHEN–dA adducts and of 4-OHEN–dC adducts in DNA. An immunoassay with 4OHEN-1 revealed a linear dose–response between known amounts of 4-OHEN–DNA adducts and the antibody binding to those adducts, with a detection limit of approximately five adducts/108 bases in 1 µg DNA sample. In human breast cancer cells, the quantitative immunoassay revealed that 4-OHEN produces five times more 4-OHEN–DNA adducts than does 4-OHEQ. Moreover, in a mouse model for HRT, oral administration of Premarin increased the levels of 4-OHEN–DNA adducts in various tissues, including the uterus and ovaries, in a time-dependent manner. Thus, we succeeded in establishing a novel immunoassay for quantitative detection of 4-OHEN–DNA adducts in mammalian cells

Alcohol consumption, endogenous estrogen and mammographic density among premenopausal women

Introduction: Alcohol consumption may promote aromatization of androgens to estrogens, which may partly explain the observations linking alcohol consumption to higher breast cancer risk. Whether alcohol consumption is associated with endogenous estrogen levels, and mammographic density phenotypes in premenopausal women remains unclear. Methods: Alcohol consumption was collected by self-report and interview, using semi quantitative food frequency questionnaires, and a food diary during seven days of a menstrual cycle among 202 premenopausal women, participating in the Energy Balance and Breast Cancer Aspects (EBBA) study I. Estrogen was assessed in serum and daily in saliva across an entire menstrual cycle. Computer-assisted mammographic density (Madena) was obtained from digitized mammograms taken between days 7–12 of the menstrual cycle. Multivariable regression models were used to investigate the associations between alcohol consumption, endogenous estrogen and mammographic density phenotypes. Results: Current alcohol consumption was positively associated with endogenous estrogen, and absolute mammographic density. We observed 18 % higher mean salivary 17β-estradiol levels throughout the menstrual cycle, among women who consumed more than 10 g of alcohol per day compared to women who consumed less than 10 g of alcohol per day (p = 0.034). Long-term and past-year alcohol consumption was positively associated with mammographic density. We observed a positive association between alcohol consumption (past year) and absolute mammographic density; high alcohol consumers (≥7 drinks/week) had a mean absolute mammographic density of 46.17 cm2 (95 % confidence interval (CI) 39.39, 52.95), while low alcohol consumers (32.4 cm2), compared to low (<1 drink/week) alcohol consumers. Conclusion: Alcohol consumption was positively associated with daily endogenous estrogen levels and mammographic density in premenopausal women. These associations could point to an important area of breast cancer prevention. Electronic supplementary material The online version of this article (doi:10.1186/s13058-015-0620-1) contains supplementary material, which is available to authorized users

The Role of Robotics in Achieving the United Nations Sustainable Development Goals-The Experts' Meeting at the 2021 IEEE/RSJ IROS Workshop

The development and deployment of robotic technologies can have an important role in efforts to achieve the United Nations' (UN) Sustainable Development Goals (SDGs) - with both enabling and inhibiting impacts. During a workshop at the 2021 IEEE/Robotics Society of Japan International Conference on Intelligent Robots and Systems (IROS 2021), experts from various disciplines analyzed the role of robotics in achieving the SDGs. This article provides a summary of the most important outcomes of the workshop. During the workshop panels, the variety of roles that robots can play in enabling the SDGs was underlined. The panelists discussed the challenges to the adoption of robots and to their deployment at their full potential. The probable undesirable effects of robots were also considered, and the panelists suggested approaches to correctly design SDG-relevant robotic solutions. Governance frameworks were also discussed, with respect to their contents as well as the challenges to build them. The role of military funding was briefly analyzed. Finally, several proposals for actions and policies were made. The contents of the workshop, including contributing papers and videos from the panelists, as well as additional information about future initiatives regarding robotics and the SDGs, are available at www.sustainablerobotics.org

Integrating Web services and Software Agents for Tailorable Groupware Design

We present a new groupware architecture model called UD 3 that explicitly introduces the notion of tailorability in designing collaborative applications. This model is based on the integration of web services and software agents technologies, thus using protocols of each while reinforcing their individual strengths in the context of tailorable groupware design. In our work, web services are dynamically invoked by software agents in order to bring new behaviors, and hence, enhancing the collaboration process by dynamically adapting the services offered in the system to the users' preferences and not the other way around. Web services and agents were originally developed with different standards, thus their integration becomes important in the context of groupware tailorability, giving a totally innovative approach in the area of CSCW (Computer Supported Cooperative Work). We apply our model on the DIGITAL OCEAN project for the creation and distribution of multimedia files on the Internet