Method of establishing breast cancer brain metastases affects brain uptake and efficacy of targeted, therapeutic nanoparticles

HER2‐targeted therapies effectively control systemic disease, but their efficacy against brain metastases is hindered by their low penetration of the blood‐brain and blood‐tumor barriers (BBB and BTB). We investigate brain uptake and antitumor efficacy of transferrin receptor (TfR)‐targeted, therapeutic nanoparticles designed to transcytose the BBB/BTB in three murine models. Two known models involving intracranial (IC) or intracardiac (ICD) injection of human breast cancer cells were employed, as was a third model developed here involving intravenous (IV) injection of the cells to form whole‐body tumors that eventually metastasize to the brain. We show the method of establishing brain metastases significantly affects therapeutic BBB/BTB penetration. Free drug accumulates and delays growth in IC‐ and ICD‐formed brain tumors, while non‐targeted nanoparticles show uptake and inhibition only in IC‐established metastases. TfR‐targeted nanoparticles accumulate and significantly delay growth in all three models, suggesting the IV model maintains a more intact BBB/BTB than the other models

Targeted Nanoparticle Delivery of Therapeutics Across the Blood-Brain and Blood-Tumor Barriers to Breast Cancer Brain Metastases

Brain metastases of human epidermal growth factor receptor 2 (HER2)-positive breast cancer are presenting an increasing problem in the clinic. While HER2-targeted therapies effectively control systemic disease, their efficacy against brain metastases is hindered by their inability to penetrate the blood-brain and blood-tumor barriers (BBB and BTB). One promising strategy to increase brain penetration of systemic therapeutics is to exploit endogenous transport systems at the BBB to shuttle drugs into the brain. Previous studies showed that gold nanoparticles designed to shed transferrin receptor (TfR)-targeting ligands under acidic conditions encountered during transcytosis of the BBB demonstrated increased accumulation in the brain. The focus of this work was to determine whether therapeutic, TfR-targeted nanoparticles using an improved acid-cleavable chemistry could be used to deliver therapeutically useful amounts of drug to the brain. To accomplish this goal, a new animal model of HER2-positive breast cancer brain metastasis was developed in an attempt to create a clinically representative, impermeable barrier to standard therapeutics. This new model establishes brain metastases by methods that more closely resemble the human disease, forming whole-body tumors that eventually metastasize to the brain. Brain metastases formed by this new methodology show no response to standard HER2-targeted agents, mimicking the clinical situation. Next, efficacy and brain uptake of TfR-targeted, single-agent therapeutic nanoparticles were investigated in the newly developed model, as well as two common models from the literature. These nanoparticles show significant tumor growth delay and increased accumulation in both brain metastases and healthy brain tissue in all three models, highlighting their therapeutic potential. Additionally, non-BBB-penetrant small molecule and non-targeted nanoparticle therapeutics elicit a substantial antitumor response as well as brain tumor accumulation in the most commonly used literature model. In contrast, the new model and one gaining popularity in the literature provide for a more clinically relevant, impermeable barrier to non-BBB-penetrant agents, indicating that the method used to establish brain metastases can affect efficacy and brain uptake of therapeutics.</p

Perioperative management of patients on warfarin and the new oral anticoagulants

This article is freely available via Open Access. Click on the 'Additional Link' above to download a PDF of the whole issue.Open Acces

Cerebral challenge

This article is freely available via Open Access. Click on the 'Additional Link' above to download the PDF of the whole issue.Open acces

Method of establishing breast cancer brain metastases affects brain uptake and efficacy of targeted, therapeutic nanoparticles

HER2‐targeted therapies effectively control systemic disease, but their efficacy against brain metastases is hindered by their low penetration of the blood‐brain and blood‐tumor barriers (BBB and BTB). We investigate brain uptake and antitumor efficacy of transferrin receptor (TfR)‐targeted, therapeutic nanoparticles designed to transcytose the BBB/BTB in three murine models. Two known models involving intracranial (IC) or intracardiac (ICD) injection of human breast cancer cells were employed, as was a third model developed here involving intravenous (IV) injection of the cells to form whole‐body tumors that eventually metastasize to the brain. We show the method of establishing brain metastases significantly affects therapeutic BBB/BTB penetration. Free drug accumulates and delays growth in IC‐ and ICD‐formed brain tumors, while non‐targeted nanoparticles show uptake and inhibition only in IC‐established metastases. TfR‐targeted nanoparticles accumulate and significantly delay growth in all three models, suggesting the IV model maintains a more intact BBB/BTB than the other models

Impact of a College Freshman Social and Emotional Learning Curriculum on Student Learning Outcomes: An Exploratory Study

This study investigates the impact of implementing a social and emotional learning curriculum for college freshmen on student learning outcomes, including social and emotional competence and academic performance. Through the use of a quasi-experimental design, the growth in social and emotional competence of students who participated in the social and emotional learning seminars is compared with that of students who were enrolled in other freshman seminars. This comparison is complemented by a qualitative analysis of students’ self-reflections in relation to specific dimensions of social and emotional competence. The results of this study suggest that exposure to a social and emotional learning curriculum during the first semester at college may contribute to the development of social and emotional competence in students. Because of the potential relationship of social and emotional competence to academic success, this study also reports a comparison of the grade point averages (GPAs) of students from the social and emotional seminars with the GPAs of students from the other freshman seminars, while controlling for other predictors of academic success. The results indicate that students exposed to the social and emotional learning curriculum had higher grades than other students across the four semesters following the completion of the seminar

Recommendations for​ Wildfire Recovery Planning for the City of Arcata

Western landscapes are experiencing an increased scale and intensity of wildfires, due in part to climate change, fire suppression, and an expanding wildland-urban interface. The damage to human lives and property caused by wildfires has prompted all levels of government to galvanize planning efforts to better respond to and recover from wildfire. This report summarizes the need for effective wildfire recovery planning for the City of Arcata, California. The city is currently working on its Hazard Mitigation Plan to be eligible for funding under FEMA hazard mitigation grant programs. This report seeks to inform the city by highlighting the importance of incorporating recovery planning into the Hazard Mitigation Plan. Research was conducted via review of other plans and interviews of officials and those affected by wildfires. The gathered information was used to identify current short and long-term resources that exist for the recovery of residents, businesses, and schools. Through this process gaps in current wildfire recovery resources were identified and this information was used to make recommendations to the City of Arcata for their Hazard Mitigation Plan. Recommendations include drafting a comprehensive debris removal plan, having a plan to disseminate information to affected persons, and identifying areas where temporary housing could be erected

Caring, Investing, Empowering: Undergraduate Research Mentoring Practices by English Faculty

Mentoring undergraduate research has received attention in scholarly publications, particularly in STEM areas (Pierszalowski & Buser, 2021; National Academies; Pathways to Science). More general advice on mentoring appears in Temple et al (2010) and Vandermaas-Peeler et al, 2018). Attention to mentoring undergraduate researchers in the humanities has been addressed by Behling (2009), Klos, et al (2011), Crawford et al (2014). Grobman and Kinkead (2010) include a section on mentoring in their Undergraduate Research in English Studies. What are the characteristics of faculty mentors in a department of English? This study seeks to determine a profile of effective mentoring in this discipline. Do these characteristics match those identified by Shanahan, et al (2015) in their comprehensive review of literature, “Ten Salient Practices of Undergraduate Mentors: A Review of the Literature”

The effect of an exopolysaccharide probiotic molecule from Bacillus subtilis on breast cancer cells

IntroductionMany well-known risk factors for breast cancer are associated with dysbiosis (an aberrant microbiome). However, how bacterial products modulate cancer are poorly understood. In this study, we investigated the effect of an exopolysaccharide (EPS) produced by the commensal bacterium Bacillus subtilis on breast cancer phenotypes. Although B. subtilis is commonly included in probiotic preparations and its EPS protects against inflammatory diseases, it was virtually unknown whether B. subtilis-derived EPS affects cancer.MethodsThis work investigated effects of EPS on phenotypes of breast cancer cells as a cancer model. The phenotypes included proliferation, mammosphere formation, cell migration, and tumor growth in two immune compromised mouse models. RNA sequencing was performed on RNA from four breast cancer cells treated with PBS or EPS. IKKβ or STAT1 signaling was assessed using pharmacologic or RNAi-mediated knock down approaches. ResultsShort-term treatment with EPS inhibited proliferation of certain breast cancer cells (T47D, MDA-MB-468, HCC1428, MDA-MB-453) while having little effect on others (MCF-7, MDA-MB-231, BT549, ZR-75-30). EPS induced G1/G0 cell cycle arrest of T47D cells while increasing apoptosis of MDA-MB-468 cells. EPS also enhanced aggressive phenotypes in T47D cells including cell migration and cancer stem cell survival. Long-term treatment with EPS (months) led to resistance in vitro and promoted tumor growth in immunocompromised mice. RNA-sequence analysis showed that EPS increased expression of pro-inflammatory pathways including STAT1 and NF-κB. IKKβ and/or STAT1 signaling was necessary for EPS to modulate phenotypes of EPS sensitive breast cancer cells. DiscussionThese results demonstrate a multifaceted role for an EPS molecule secreted by the probiotic bacterium B. subtilis on breast cancer cell phenotypes. These results warrant future studies in immune competent mice and different cancer models to fully understand potential benefits and/or side effects of long-term use of probiotics

Historic Millyard Revitalization Project: Ware, MA

This project’s mission is to provide an all- encompassing destination for the needs of current and future employees, residents, and visitors of the Ware Millyard Historic District and the community of Ware, MA. The project aims to facilitate the revitalization and redevelopment of the Millyard and develop a communal campus which provides employment, housing, goods, services, as well as recreational and social opportunities for the region. The vision of this project is to facilitate the revitalization and redevelopment of the Ware Millyard Historic District by establishing an emerging industry within the site. Incorporating the cannabis industry and all of its major types of establishments throughout the site will provide the cornerstone component while offering new opportunities as a catalyst for other industries