Abrogation of Junctional Adhesion Molecule-A Expression Induces Cell Apoptosis and Reduces Breast Cancer Progression

Intercellular junctions promote homotypic cell to cell adhesion and transfer intracellular signals which control cell growth and apoptosis. Junctional adhesion molecule-A (JAM-A) is a transmembrane immunoglobulin located at tight junctions of normal epithelial cells of mammary ducts and glands. In the present paper we show that JAM-A acts as a survival factor for mammary carcinoma cells. JAM-A null mice expressing Polyoma Middle T under MMTV promoter develop significantly smaller mammary tumors than JAM-A positive mice. Angiogenesis and inflammatory or immune infiltrate were not statistically modified in absence of JAM-A but tumor cell apoptosis was significantly increased. Tumor cells isolated from JAM-A null mice or 4T1 cells incubated with JAM-A blocking antibodies showed reduced growth and increased apoptosis which paralleled altered junctional architecture and adhesive function. In a breast cancer clinical data set, tissue microarray data show that JAM-A expression correlates with poor prognosis. Gene expression analysis of mouse tumor samples showed a correlation between genes enriched in human G3 tumors and genes over expressed in JAM-A +/+ mammary tumors. Conversely, genes enriched in G1 human tumors correlate with genes overexpressed in JAM-A−/− tumors. We conclude that down regulation of JAM-A reduces tumor aggressive behavior by increasing cell susceptibility to apoptosis. JAM-A may be considered a negative prognostic factor and a potential therapeutic target

Report of the 1st Workshop on Generative AI and Law

This report presents the takeaways of the inaugural Workshop on Generative AI and Law (GenLaw), held in July 2023. A cross-disciplinary group of practitioners and scholars from computer science and law convened to discuss the technical, doctrinal, and policy challenges presented by law for Generative AI, and by Generative AI for law, with an emphasis on U.S. law in particular. We begin the report with a high-level statement about why Generative AI is both immensely significant and immensely challenging for law. To meet these challenges, we conclude that there is an essential need for 1) a shared knowledge base that provides a common conceptual language for experts across disciplines; 2) clarification of the distinctive technical capabilities of generative-AI systems, as compared and contrasted to other computer and AI systems; 3) a logical taxonomy of the legal issues these systems raise; and, 4) a concrete research agenda to promote collaboration and knowledge-sharing on emerging issues at the intersection of Generative AI and law. In this report, we synthesize the key takeaways from the GenLaw workshop that begin to address these needs. All of the listed authors contributed to the workshop upon which this report is based, but they and their organizations do not necessarily endorse all of the specific claims in this report

Barriers and enablers to delivery of the Healthy Kids Check: An analysis informed by the Theoretical Domains Framework and COM-B model

Background: More than a fifth of Australian children arrive at school developmentally vulnerable. To counteract this, the Healthy Kids Check (HKC), a one-off health assessment aimed at preschool children, was introduced in 2008 into Australian general practice. Delivery of services has, however, remained low. The Theoretical Domains Framework, which provides a method to understand behaviours theoretically, can be condensed into three core components: capability, opportunity and motivation, and the COM-B model. Utilising this system, this study aimed to determine the barriers and enablers to delivery of the HKC, to inform the design of an intervention to promote provision of HKC services in Australian general practice. Methods: Data from 6 focus group discussions with 40 practitioners from general practices in socio-culturally diverse areas of Melbourne, Victoria, were analysed using thematic analysis. Results: Many practitioners expressed uncertainty regarding their capabilities and the practicalities of delivering HKCs, but in some cases HKCs had acted as a catalyst for professional development. Key connections between immunisation services and delivery of HKCs prompted practices to have systems of recall and reminder in place. Standardisation of methods for developmental assessment and streamlined referral pathways affected practitioners' confidence and motivation to perform HKCs. Conclusion: Application of a systematic framework effectively demonstrated how a number of behaviours could be targeted to increase delivery of HKCs. Interventions need to target practice systems, the support of office staff and referral options, as well as practitioners' training. Many behavioural changes could be applied through a single intervention programme delivered by the primary healthcare organisations charged with local healthcare needs (Medicare Locals) providing vital links between general practice, community and the health of young children. © 2014 Alexander et al.; licensee BioMed Central Ltd

Breaking barriers: using the behavior change wheel to develop a tailored intervention to overcome workplace inhibitors to breaking up sitting time

© The Author(s). 2019. Background: The workplace is a prominent domain for excessive sitting. The consequences of increased sitting time include adverse health outcomes such as cardiovascular disease and poor mental wellbeing. There is evidence that breaking up sitting could improve health, however, any such intervention in the workplace would need to be informed by a theoretical evidence-based framework. The aim of this study was to use the Behaviour Change Wheel (BCW) to develop a tailored intervention to break up and reduce workplace sitting in desk-based workers. Methods: The BCW guide was followed for this qualitative, pre-intervention development study. Semi-structured interviews were conducted with 25 office workers (26–59years, mean age 40.9 [SD=10.8] years; 68% female) who were purposively recruited from local council offices and a university in the East of England region. The interview questions were developed using the Theoretical Domains Framework (TDF). Transcripts were deductively analysed using the COM-B (Capability, Opportunity, Motivation – Behaviour) model of behaviour. The Behaviour Change Technique Taxonomy Version 1 (BCTv1) was thereafter used to identify possible strategies that could be used to facilitate change in sitting behaviour of office workers in a future intervention. Results: Qualitative analysis using COM-B identified that participants felt that they had the physical Capability to break up their sitting time, however, some lacked the psychological Capability in relation to the knowledge of both guidelines for sitting time and the consequences of excess sitting. Social and physical Opportunity was identified as important, such as a supportive organisational culture (social) and the need for environmental resources (physical). Motivation was highlighted as a core target for intervention, both reflective Motivation, such as beliefs about capability and intention and automatic in terms of overcoming habit through reinforcement. Seven intervention functions and three policy categories from the BCW were identified as relevant. Finally, 39 behaviour change techniques (BCTs) were identified as potential active components for an intervention to break up sitting time in the workplace. Conclusions: The TDF, COM-B model and BCW can be successfully applied through a systematic process to understand the drivers of behaviour of office workers to develop a co-created intervention that can be used to break up and decrease sitting in the workplace. Intervention designers should consider the identified BCW factors and BCTs when developing interventions to reduce and break up workplace sitting

Tight junctions: from simple barriers to multifunctional molecular gates

Epithelia and endothelia separate different tissue compartments and protect multicellular organisms from the outside world. This requires the formation of tight junctions, selective gates that control paracellular diffusion of ions and solutes. Tight junctions also form the border between the apical and basolateral plasma-membrane domains and are linked to the machinery that controls apicobasal polarization. Additionally, signalling networks that guide diverse cell behaviours and functions are connected to tight junctions, transmitting information to and from the cytoskeleton, nucleus and different cell adhesion complexes. Recent advances have broadened our understanding of the molecular architecture and cellular functions of tight junctions

The association between the ratio of monocytes:lymphocytes at age 3 months and risk of tuberculosis (TB) in the first two years of life

BACKGROUND: Recent transcriptomic studies revived a hypothesis suggested by historical studies in rabbits that the ratio of peripheral blood monocytes to lymphocytes (ML) is associated with risk of tuberculosis (TB) disease. Recent data confirmed the hypothesis in cattle and in adults infected with HIV. METHODS: We tested this hypothesis in 1,336 infants (540 HIV-infected, 796 HIV-exposed, uninfected (HEU)) prospectively followed in a randomized controlled trial of isoniazid prophylaxis in Southern Africa, the IMPAACT P1041 study. We modeled the relationship between ML ratio at enrollment (91 to 120 days after birth) and TB disease or death in HIV-infected children and latent Mycobacterium tuberculosis (MTB) infection, TB disease or death in HEU children within 96 weeks (with 12 week window) of randomization. Infants were followed-up prospectively and routinely assessed for MTB exposure and outcomes. Cox proportional hazards models allowing for non-linear associations were used; in all cases linear models were the most parsimonious. RESULTS: Increasing ML ratio at baseline was significantly associated with TB disease/death within two years (adjusted hazard ratio (HR) 1.17 per unit increase in ML ratio; 95% confidence interval (CI) 1.01 to 1.34; P = 0.03). Neither monocyte count nor lymphocyte counts alone were associated with TB disease. The association was not statistically dissimilar between HIV infected and HEU children. Baseline ML ratio was associated with composite endpoints of TB disease and death and/or TB infection. It was strongest when restricted to probable and definite TB disease (HR 1.50; 95% CI 1.19 to 1.89; P = 0.006). Therefore, per 0.1 unit increase in the ML ratio at three to four months of age, the hazard of probable or definite TB disease before two years was increased by roughly 4% (95% CI 1.7% to 6.6%). CONCLUSION: Elevated ML ratio at three- to four-months old is associated with increased hazards of TB disease before two years among children in Southern Africa. While significant, the modest effect size suggests that the ML ratio plays a modest role in predicting TB disease-free survival; its utility may, therefore, be limited to combination with existing tools to stratify TB risk, or to inform underlying pathophysiologic determinants of TB disease

An investigation into the spiritual needs of neuro-oncology patients from a nurse perspective

Background: Spiritual needs of cancer patients should be assessed and discussed by healthcare professionals. Neurosurgical nurses need to be able to assess and support neuro-oncology patients with their spiritual needs from diagnosis and throughout their hospital stay. Methods: Data were collected through questionnaires using a Critical Incident Technique (CIT) from neurosurgical nurses, findings were analysed using thematic analysis. Results: Nurses reported some awareness of their patients’ spiritual needs during their stay on neurosurgical units although some used expressions approximating what could be described as spiritual needs. Patients’ spiritual needs were identified as: need to talk about spiritual concerns, showing sensitivity to patients’ emotions, responding to religious needs; and relatives’ spiritual needs included: supporting them with end of life decisions, supporting them when feeling being lost and unbalanced, encouraging exploration of meaning of life, and providing space, time and privacy to talk. Participants appeared largely to be in tune with their patients’ spiritual needs and reported that they recognised effective strategies to meet their patients’ and relatives’ spiritual needs. However, the findings also suggest that they don’t always feel prepared to offer spiritual support for neuro-oncology patients. Conclusions: There is a need for healthcare professionals to provide spiritual care for neuro-oncology patients and their relatives. Although strategies were identified that nurses can use to support patients with spiritual needs further research is required to explore how effective nurses are at delivering spiritual care and if nurses are the most appropriate professionals to support neuro-oncology patients with spiritual care