A 3D in vitro model of the human breast duct:A method to unravel myoepithelial-luminal interactions in the progression of breast cancer

Abstract Background 3D modelling fulfils a critical role in research, allowing for complex cell behaviour and interactions to be studied in physiomimetic conditions. With tissue banks becoming established for a number of cancers, researchers now have access to primary patient cells, providing the perfect building blocks to recreate and interrogate intricate cellular systems in the laboratory. The ducts of the human breast are composed of an inner layer of luminal cells supported by an outer layer of myoepithelial cells. In early-stage ductal carcinoma in situ, cancerous luminal cells are confined to the ductal space by an intact myoepithelial layer. Understanding the relationship between myoepithelial and luminal cells in the development of cancer is critical for the development of new therapies and prognostic markers. This requires the generation of new models that allows for the manipulation of these two cell types in a physiological setting. Methods Using access to the Breast Cancer Now Tissue Bank, we isolated pure populations of myoepithelial and luminal cells from human reduction mammoplasty specimens and placed them into 2D culture. These cells were infected with lentiviral particles encoding either fluorescent proteins, to facilitate cell tracking, or an inducible human epidermal growth factor receptor 2 (HER2) expression construct. Myoepithelial and luminal cells were then recombined in collagen gels, and the resulting cellular structures were analysed by confocal microscopy. Results Myoepithelial and luminal cells isolated from reduction mammoplasty specimens can be grown separately in 2D culture and retain their differentiated state. When recombined in collagen gels, these cells reform into physiologically reflective bilayer structures. Inducible expression of HER2 in the luminal compartment, once the bilayer has formed, leads to robust luminal filling, recapitulating ductal carcinoma in situ, and can be blocked with anti-HER2 therapies. Conclusions This model allows for the interaction between myoepithelial and luminal cells to be investigated in an in-vitro environment and paves the way to study early events in breast cancer development with the potential to act as a powerful drug discovery platform

State of Nonprofits Annual Report: 2013

It is hard to believe, but prior to the Caster Center’s first publication in 2006, A Spotlight on San Diego’s Third Sector, nobody knew how many nonprofits were located in San Diego County, let alone anything about their major activities, capacity, or contributions to our larger economy. Since that time, the Caster Center team has been pushing the boundaries of nonprofit data collection to tell the sector’s story in a more timely, complete, and meaningful way. This report represents a new milestone in these ongoing efforts. Much has transpired since the publication of the Center’s first report, not only in the nonprofit sector, but also in the lives of the 3 million San Diegans served by these organizations. Together we have weathered the most challenging economic conditions since the Great Depression and are adapting to its myriad and lasting effects. And, although it appears that the worst is behind us, our community and its organizations are forever changed as a result. This report chronicles the economic health and well-being of San Diego’s nonprofit sector over that time and documents the current state of the sector as expressed by its leaders.https://digital.sandiego.edu/npi-stateofnp/1000/thumbnail.jp

State of Nonprofits Annual Report: 2013

It is hard to believe, but prior to the Caster Center’s first publication in 2006, A Spotlight on San Diego’s Third Sector, nobody knew how many nonprofits were located in San Diego County, let alone anything about their major activities, capacity, or contributions to our larger economy. Since that time, the Caster Center team has been pushing the boundaries of nonprofit data collection to tell the sector’s story in a more timely, complete, and meaningful way. This report represents a new milestone in these ongoing efforts. Much has transpired since the publication of the Center’s first report, not only in the nonprofit sector, but also in the lives of the 3 million San Diegans served by these organizations. Together we have weathered the most challenging economic conditions since the Great Depression and are adapting to its myriad and lasting effects. And, although it appears that the worst is behind us, our community and its organizations are forever changed as a result. This report chronicles the economic health and well-being of San Diego’s nonprofit sector over that time and documents the current state of the sector as expressed by its leaders.https://digital.sandiego.edu/npi-stateofnp/1000/thumbnail.jp

Loss of life at sea from shipping British coal since 1890

There was continuing public and political concern about the loss of life at sea during the second half of the nineteenth century in Britain. New regulatory requirements, introduced to examine the competence of officers, prevent overloading and reduce the risks from hazardous cargoes such as coal, were in place by 1890. However, the effectiveness of these measures was not systematically monitored at the time. This retrospective evaluation reviews subsequent loss of life in the coal trade, the largest sector of British exports by weight. Loss of life remained high; it was more dangerous to export a ton of coal than it was to mine it. Some routes, such as those around Cape Horn and to Scandinavia, carried the highest risk, and losses on European voyages were more common in winter. Over time, the risks reduced as sail gave way to steam and diesel propulsion, and as maritime communications improved

Parents’ experiences and perceptions of the acceptability of a whole-hospital, pro-active electronic pediatric early warning system (the DETECT study): A qualitative interview study

BackgroundFailure to recognize and respond to clinical deterioration in a timely and effective manner is an urgent safety concern, driving the need for early identification systems to be embedded in the care of children in hospital. Pediatric early warning systems (PEWS) or PEW scores alert health professionals (HPs) to signs of deterioration, trigger a review and escalate care as needed. PEW scoring allows HPs to record a child's vital signs and other key data including parent concern.AimThis study aimed to explore the experiences and perceptions of parents about the acceptability of a newly implemented electronic surveillance system (the DETECT surveillance system), and factors that influenced acceptability and their awareness around signs of clinical deterioration and raising concern.MethodsDescriptive, qualitative semi-structured telephone interviews were undertaken with parents of children who had experienced a critical deterioration event (CDE) (n = 19) and parents of those who had not experienced a CDE (non-CDE parents) (n = 17). Data were collected between February 2020 and February 2021.ResultsQualitative data were analyzed using generic thematic analysis. Analysis revealed an overarching theme of trust as a key factor that underpinned all aspects of children's vital signs being recorded and monitored. The main themes reflect three domains of parents' trust: trust in themselves, trust in the HPs, and trust in the technology.ConclusionParents' experiences and perceptions of the acceptability of a whole-hospital, pro-active electronic pediatric early warning system (The DETECT system) were positive; they found it acceptable and welcomed the use of new technology to support the care of their child

Clinical utility and acceptability of a whole-hospital, pro-active electronic paediatric early warning system (the DETECT study): a prospective e-survey of parents and health professionals.

BackgroundPaediatric early warning systems (PEWS) are a means of tracking physiological state and alerting healthcare professionals about signs of deterioration, triggering a clinical review and/or escalation of care of children. A proactive end-to-end deterioration solution (the DETECT surveillance system) with an embedded e-PEWS that included sepsis screening was introduced across a tertiary children's hospital. One component of the implementation programme was a sub-study to determine an understanding of the DETECT e-PEWS in terms of its clinical utility and its acceptability.AimThis study aimed to examine how parents and health professionals view and engage with the DETECT e-PEWS apps, with a particular focus on its clinical utility and its acceptability.MethodA prospective, closed (tick box or sliding scale) and open (text based) question, e-survey of parents (n = 137) and health professionals (n = 151) with experience of DETECT e-PEWS. Data were collected between February 2020 and February 2021.ResultsQuantitative data were analysed using descriptive and inferential statistics and qualitative data with generic thematic analysis. Overall, both clinical utility and acceptability (across seven constructs) were high across both stakeholder groups although some challenges to utility (e.g., sensitivity of triggers within specific patient populations) and acceptability (e.g., burden related to having to carry extra technology) were identified.ConclusionDespite the multifaceted nature of the intervention and the complexity of implementation across a hospital, the system demonstrated clinical utility and acceptability across two key groups of stakeholders: parents and health professionals

Towards defining reference materials for extracellular vesicle size, concentration, refractive index and epitope abundance

Accurate characterization of extracellular vesicles (EVs) is critical to explore their diagnostic and therapeutic applications. As the EV research field has developed, so too have the techniques used to characterize them. The development of reference materials is required for the standardization of these techniques. This work, initiated from the ISEV 2017 Biomarker Workshop in Birmingham, UK, and with further discussion during the ISEV 2019 Standardization Workshop in Ghent, Belgium, sets out to elucidate which reference materials are required and which are currently available to standardize commonly used analysis platforms for characterizing EV size, concentration, refractive index, and epitope expression. Due to their predominant use, a particular focus is placed on the optical methods nanoparticle tracking analysis and flow cytometry.Comment: 30 pages, 6 figures, 2 table

Characteristics of patients in platform C19, a COVID-19 research database combining primary care electronic health record and patient reported information

Background Data to better understand and manage the COVID-19 pandemic is urgently needed. However, there are gaps in information stored within even the best routinely-collected electronic health records (EHR) including test results, remote consultations for suspected COVID-19, shielding, physical activity, mental health, and undiagnosed or untested COVID-19 patients. Observational and Pragmatic Research Institute (OPRI) Singapore and Optimum Patient Care (OPC) UK established Platform C19, a research database combining EHR data and bespoke patient questionnaire. We describe the demographics, clinical characteristics, patient behavior, and impact of the COVID-19 pandemic using data within Platform C19. Methods EHR data from Platform C19 were extracted from 14 practices across UK participating in the OPC COVID-19 Quality Improvement program on a continuous, monthly basis. Starting 7th August 2020, consenting patients aged 18–85 years were invited in waves to fill an online questionnaire. Descriptive statistics were summarized using all data available up to 22nd January 2021. Findings From 129,978 invitees, 31,033 responded. Respondents were predominantly female (59.6%), white (93.5%), and current or ex-smokers (52.6%). Testing for COVID-19 was received by 23.8% of respondents, of which 7.9% received positive results. COVID-19 symptoms lasted ≥4 weeks in 19.5% of COVID-19 positive respondents. Up to 39% respondents reported a negative impact on questions regarding their mental health. Most (67%-76%) respondents with asthma, Chronic Obstructive Pulmonary Disease (COPD), diabetes, heart, or kidney disease reported no change in the condition of their diseases. Interpretation Platform C19 will enable research on key questions relating to COVID-19 pandemic not possible using EHR data alone

Placental syncytiotrophoblast constitutes a major barrier to vertical transmission of Listeria monocytogenes.

Listeria monocytogenes is an important cause of maternal-fetal infections and serves as a model organism to study these important but poorly understood events. L. monocytogenes can infect non-phagocytic cells by two means: direct invasion and cell-to-cell spread. The relative contribution of each method to placental infection is controversial, as is the anatomical site of invasion. Here, we report for the first time the use of first trimester placental organ cultures to quantitatively analyze L. monocytogenes infection of the human placenta. Contrary to previous reports, we found that the syncytiotrophoblast, which constitutes most of the placental surface and is bathed in maternal blood, was highly resistant to L. monocytogenes infection by either internalin-mediated invasion or cell-to-cell spread. Instead, extravillous cytotrophoblasts-which anchor the placenta in the decidua (uterine lining) and abundantly express E-cadherin-served as the primary portal of entry for L. monocytogenes from both extracellular and intracellular compartments. Subsequent bacterial dissemination to the villous stroma, where fetal capillaries are found, was hampered by further cellular and histological barriers. Our study suggests the placenta has evolved multiple mechanisms to resist pathogen infection, especially from maternal blood. These findings provide a novel explanation why almost all placental pathogens have intracellular life cycles: they may need maternal cells to reach the decidua and infect the placenta

3D Selection of 167 Substellar Companions to Nearby Stars

© 2022. The Author(s). Published by the American Astronomical Society. This is an open access article distributed under the Creative Commons Attribution License, to view a copy of the license, see: https://creativecommons.org/licenses/by/4.0/We analyze 5108 AFGKM stars with at least five high-precision radial velocity points, as well as Gaia and Hipparcos astrometric data, utilizing a novel pipeline developed in previous work. We find 914 radial velocity signals with periods longer than 1000 days. Around these signals, 167 cold giants and 68 other types of companions are identified, through combined analyses of radial velocity, astrometry, and imaging data. Without correcting for detection bias, we estimate the minimum occurrence rate of the wide-orbit brown dwarfs to be 1.3%, and find a significant brown-dwarf valley around 40 M Jup. We also find a power-law distribution in the host binary fraction beyond 3 au, similar to that found for single stars, indicating no preference of multiplicity for brown dwarfs. Our work also reveals nine substellar systems (GJ 234 B, GJ 494 B, HD 13724 b, HD 182488 b, HD 39060 b and c, HD 4113 C, HD 42581 d, HD 7449 B, and HD 984 b) that have previously been directly imaged, and many others that are observable at existing facilities. Depending on their ages, we estimate that an additional 10–57 substellar objects within our sample can be detected with current imaging facilities, extending the imaged cold (or old) giants by an order of magnitude.Peer reviewe