Engineering immune-evasive allogeneic cellular immunotherapies.

Allogeneic cellular immunotherapies hold a great promise for cancer treatment owing to their potential cost-effectiveness, scalability and on-demand availability. However, immune rejection of adoptively transferred allogeneic T and natural killer (NK) cells is a substantial obstacle to achieving clinical responses that are comparable to responses obtained with current autologous chimeric antigen receptor T cell therapies. In this Perspective, we discuss strategies to confer cell-intrinsic, immune-evasive properties to allogeneic T cells and NK cells in order to prevent or delay their immune rejection, thereby widening the therapeutic window. We discuss how common viral and cancer immune escape mechanisms can serve as a blueprint for improving the persistence of off-the-shelf allogeneic cell therapies. The prospects of harnessing genome editing and synthetic biology to design cell-based precision immunotherapies extend beyond programming target specificities and require careful consideration of innate and adaptive responses in the recipient that may curtail the biodistribution, in vivo expansion and persistence of cellular therapeutics.

Development and Evaluation of Surveillance System for Identifying Jail-Associated COVID-19 Cases in Minnesota, USA, 2022.

Confinement facilities are high-risk settings for the spread of infectious disease, necessitating timely surveillance to inform public health action. To identify jail-associated COVID-19 cases from electronic laboratory reports maintained in the Minnesota Electronic Disease Surveillance System (MEDSS), Minnesota, USA, the Minnesota Department of Health developed a surveillance system that used keyword and address matching (KAM). The KAM system used a SAS program (SAS Institute Inc., https://www.sas.com) and an automated program within MEDSS to identify confinement keywords and addresses. To evaluate KAM, we matched jail booking data from the Minnesota Statewide Supervision System by full name and birthdate to the MEDSS records of adults with COVID-19 for 2022. The KAM system identified 2,212 cases in persons detained in jail; sensitivity was 92.40% and specificity was 99.95%. The success of KAM demonstrates its potential to be applied to other diseases and congregate-living settings for real-time surveillance without added reporting burden.

Genetic ablation of adhesion ligands averts rejection of allogeneic immune cells.

Allogeneic cell therapies hold promise for broad clinical implementation, but face limitations due to potential rejection by the recipient immune system. Silencing of beta-2-microglobulin ( B2M ) expression is commonly employed to evade T cell-mediated rejection, although absence of B2M triggers missing-self responses by recipient natural killer (NK) cells. Here, we demonstrate that deletion of the adhesion ligands CD54 and CD58 on targets cells robustly dampens NK cell reactivity across all sub-populations. Genetic deletion of CD54 and CD58 in B2M -deficient allogeneic chimeric antigen receptor (CAR) T and multi-edited induced pluripotent stem cell (iPSC)-derived NK cells reduces their susceptibility to rejection by NK cells in vitro and in vivo without affecting their anti-tumor effector potential. Thus, these data suggest that genetic ablation of adhesion ligands effectively alleviates rejection of allogeneic immune cells for immunotherapy.

Delayed graft rejection in autoimmune islet transplantation via biomaterial immunotherapy.

The induction of operational immune tolerance is a major goal in beta-cell replacement strategies for the treatment of type 1 diabetes. Our group previously reported long-term efficacy via biomaterial-mediated programmed death ligand 1 (PD-L1) immunotherapy in islet allografts in nonautoimmune models. In this study, we evaluated autoimmune recurrence and allograft rejection during islet transplantation in spontaneous nonobese diabetic (NOD) mice. Graft survival and metabolic function were significantly prolonged over 60 days in recipients of syngeneic islets receiving the biomaterial-delivered immunotherapy, but not in control animals. The biomaterial-mediated PD-L1 immunotherapy resulted in delayed allograft rejection in diabetic NOD mice compared with controls. Discrimination between responders and nonresponders was attributed to the enriched presence of CD206+ program death 1+ macrophages and exhausted signatures in the cytotoxic T cell compartment in the local graft microenvironment. Notably, draining lymph nodes had similar remodeling in innate and adaptive immune cell populations. This work establishes that our biomaterial platform for PD-L1 delivery can modulate immune responses to transplanted islets in diabetic NOD mice and, thus, can provide a platform for the development of immunologic strategies to curb the allo- and autoimmune processes in beta-cell transplant recipients.

Targeted Investigational Oncology Agents in the NCI-60: A Phenotypic Systems-based Resource.

The NCI-60 human tumor cell line panel has proved to be a useful tool for the global cancer research community in the search for novel chemotherapeutics. The publicly available cell line characterization and compound screening data from the NCI-60 assay have significantly contributed to the understanding of cellular mechanisms targeted by new oncology agents. Signature sensitivity/resistance patterns generated for a given chemotherapeutic agent against the NCI-60 panel have long served as fingerprint presentations that encompass target information and the mechanism of action associated with the tested agent. We report the establishment of a new public NCI-60 resource based on the cell line screening of a large and growing set of 175 FDA-approved oncology drugs (AOD) plus >825 clinical and investigational oncology agents (IOA), representing a diverse set (>250) of therapeutic targets and mechanisms. This data resource is available to the public (https://ioa.cancer.gov) and includes the raw data from the screening of the IOA and AOD collection along with an extensive set of visualization and analysis tools to allow for comparative study of individual test compounds and multiple compound sets.

Hydrolytic hydrogels tune mesenchymal stem cell persistence and immunomodulation for enhanced diabetic cutaneous wound healing.

Diabetes is associated with an altered global inflammatory state with impaired wound healing. Mesenchymal stem/stromal cells (MSC) are being explored for treatment of diabetic cutaneous wounds due to their regenerative properties. These cells are commonly delivered by injection, but the need to prolong the retention of MSC at sites of injury has spurred the development of biomaterial-based MSC delivery vehicles. However, controlling biomaterial degradation rates in vivo remains a therapeutic-limiting challenge. Here, we utilize hydrolytically degradable ester linkages to engineer synthetic hydrogels with tunable in vivo degradation kinetics for temporally controlled delivery of MSC. In vivo hydrogel degradation rate can be controlled by altering the ratio of ester to amide linkages in the hydrogel macromers. These hydrolytic hydrogels degrade at rates that enable unencumbered cutaneous wound healing, while enhancing the local persistence MSC compared to widely used protease-degradable hydrogels. Furthermore, hydrogel-based delivery of MSC modulates local immune responses and enhances cutaneous wound repair in diabetic mice. This study introduces a simple strategy for engineering tunable degradation modalities into synthetic biomaterials, overcoming a key barrier to their use as cell delivery vehicles.

Examining standardized consumer-generated social determinants of health and resilience data supported by Omaha System terminology.

Nursing terminologies like the Omaha System are foundational in realizing the vision of formal representation of social determinants of health (SDOH) data and whole-person health across biological, behavioral, social, and environmental domains. This study objective was to examine standardized consumer-generated SDOH data and resilience (strengths) using the MyStrengths+MyHealth (MSMH) app built using Omaha System. Overall, 19 SDOH concepts were analyzed including 19 Strengths, 175 Challenges, and 76 Needs with additional analysis around Income Challenges. Data from 919 participants presented an average of 11(SD = 6.1) Strengths, 21(SD = 15.8) Challenges, and 15(SD = 14.9) Needs. Participants with at least one Income Challenge (n = 573) had significantly (P < .001) less Strengths [9.4(6.4)], more Challenges [27.4(15.5)], and more Needs [15.1(14.9)] compared to without an Income Challenge (n = 337) Strengths [13.4(4.5)], Challenges [10.5(8.9)], and Needs [5.1(10.0)]. This standards-based approach to examining consumer-generated SDOH and resilience data presents a great opportunity in understanding 360-degree whole-person health as a step towards addressing health inequities.

Chemotherapy-induced PDL-1 expression in cancer-associated fibroblasts promotes chemoresistance in NSCLC.

OBJECTIVES: A cure for cancer is out of reach for most patients due to chemoresistance. Cancer-associated fibroblasts (CAFs) play a vital role in cancer chemoresistance, but detailed understanding of the process particularly in chemoresistant lung cancer is lacking. In this study, we investigated programmed death-ligand 1 (PDL-1) as a potential biomarker for CAF-induced chemoresistance and evaluated its role and the underlying mechanisms of chemoresistance in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: A systemic search of gene expression profiles of multiple tissues in NSCLC was carried out to determine the expression intensities of traditional fibroblast biomarkers and CAF-secreted protumorigenic cytokines. PDL-1 expression in CAFs was analyzed by ELISA, Western blotting, and flow cytometry. Human cytokine array was used to identify specific cytokines secreted from CAFs. Role of PDL-1 in NSCLC chemoresistance was assessed using CRISPR/Cas9 knockdown and various functional assays including MTT, cell invasion, sphere formation, and cell apoptosis. In vivo experiments were conducted using a co-implantation xenograft mouse model with live cell imaging and immunohistochemistry. RESULTS: We demonstrated that chemotherapy-stimulated CAFs promoted tumorigenic and stem cell-like properties of NSCLC cells, which contribute to their chemoresistance. Subsequently, we revealed that PDL-1 expression is upregulated in chemotherapy-treated CAFs and is associated with poor prognosis. Silencing PDL-1 expression suppressed CAFs' ability to promote stem cell-like properties and invasiveness of lung cancer cells, favoring chemoresistance. Mechanistically, an upregulation of PDL-1 in chemotherapy-treated CAFs led to an increase in hepatocyte growth factor (HGF) secretion, which stimulates cancer progression, cell invasion, and stemness of lung cancer cells, while inhibiting apoptosis. CONCLUSION: Our results show that PDL-1-positive CAFs modulate stem cell-like properties of NSCLC cells by secreting elevated HGF, thereby promoting chemoresistance. Our finding supports PDL-1 in CAFs as a chemotherapy response biomarker and as a drug delivery and therapeutic target for chemoresistant NSCLC.

Measuring for primary prevention: An online survey of local community perspectives on family and domestic violence in regional Australia.

BACKGROUND: Family and domestic violence, encompassing diverse behaviours including physical, sexual, emotional and financial abuse, is endemic worldwide and has multiple adverse health and social consequences. Principal drivers include traditional gender values that disempower women. Changing these is a key prevention strategy. In Australia, high-quality national surveys provide data on public perspectives concerning family and domestic violence but may not capture community-level diversity. As part of a project for primary prevention family and domestic violence in outer regional Australia, our aims were to develop and administer a questionnaire-based survey suitable for the local community encompassing knowledge about, attitudes towards, and personal experiences of family and domestic violence, to describe and to investigate the theoretical (factor) structure and local socio-demographic predictors of responses, and to determine the extent to which the survey findings are locally distinctive. METHODS: The online community survey for local residents (≥15 years), comprised items on respondents' sociodemographic characteristics plus questions abridged from pre-existing national instruments on knowledge about, attitudes towards, and personal experiences of family and domestic violence. Responses were rake-weighted to correct census-ascertained sample imbalance and investigated using exploratory factor analysis, with sociodemographic predictors determined using multiple linear regression and dominance analysis. RESULTS: Among 914 respondents, males (27.0%), those from age-group extremes, and less-educated persons were underrepresented. Familiarity with diverse family and domestic violence behaviours was high among all subgroups. Poorer knowledge of the FDV behaviour continuum and attitudes supporting traditional gender roles and FDV were disproportionately evident among males, older respondents and those with lower education levels. Both the factor structure of extracted composite measures reflecting community perspectives and sociodemographic predictors of responses generally aligned with patterns evident in national data. CONCLUSIONS: Local reinforcement of existing nationwide findings on community understanding of and attitudes towards family and domestic violence provides salience for targeted interventions.

Combinatorial treatment rescues tumour-microenvironment-mediated attenuation of MALT1 inhibitors in B-cell lymphomas.

Activated B-cell-like diffuse large B-cell lymphomas (ABC-DLBCLs) are characterized by constitutive activation of nuclear factor κB driven by the B-cell receptor (BCR) and Toll-like receptor (TLR) pathways. However, BCR-pathway-targeted therapies have limited impact on DLBCLs. Here we used >1,100 DLBCL patient samples to determine immune and extracellular matrix cues in the lymphoid tumour microenvironment (Ly-TME) and built representative synthetic-hydrogel-based B-cell-lymphoma organoids accordingly. We demonstrate that Ly-TME cellular and biophysical factors amplify the BCR-MYD88-TLR9 multiprotein supercomplex and induce cooperative signalling pathways in ABC-DLBCL cells, which reduce the efficacy of compounds targeting the BCR pathway members Bruton tyrosine kinase and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1). Combinatorial inhibition of multiple aberrant signalling pathways induced higher antitumour efficacy in lymphoid organoids and implanted ABC-DLBCL patient tumours in vivo. Our studies define the complex crosstalk between malignant ABC-DLBCL cells and Ly-TME, and provide rational combinatorial therapies that rescue Ly-TME-mediated attenuation of treatment response to MALT1 inhibitors.

Chemotherapeutic Activity of Pitavastatin in Vincristine Resistant B-Cell Acute Lymphoblastic Leukemia.

B-cell acute lymphoblastic leukemia (ALL) is derived from an accumulation of malignant, immature B cells in the bone marrow and blood. Relapse due, in part, to the emergence of tumor cells that are resistant to front line standard chemotherapy is associated with poor patient outcomes. This challenge highlights the need for new treatment strategies to eliminate residual chemoresistant tumor cells. Based on the use of pitavastatin in acute myeloid leukemia (AML), we evaluated its efficacy in an REH ALL cell line derived to be resistant to vincristine. We found that pitavastatin inhibited the proliferation of both parental and vincristine-resistant REH tumor cells at an IC50 of 449 nM and 217 nM, respectively. Mitochondrial bioenergetic assays demonstrated that neither vincristine resistance nor pitavastatin treatment affected cellular oxidative phosphorylation, beta-oxidation, or glycolytic metabolism in ALL cells. In a co-culture model of ALL cells with bone marrow stromal cells, pitavastatin significantly decreased cell viability more robustly in the vincristine-resistant ALL cells compared with their parental controls. Subsequently, NSG mice were used to develop an in vivo model of B-cell ALL using both parental and vincristine-resistant ALL cells. Pitavastatin (10 mg/kg i.p.) significantly reduced the number of human CD45+ REH ALL cells in the bone marrow of mice after 4 weeks of treatment. Mechanistic studies showed that pitavastatin treatment in the vincristine-resistant cells led to apoptosis, with increased levels of cleaved PARP and protein-signaling changes for AMP-activated protein kinase/FoxO3a/Puma. Our data suggest the possible repurposing of pitavastatin as a chemotherapeutic agent in a model of vincristine-resistant B-cell ALL.

Creating a quadruple aim model for nursing education.

Baccalaureate nursing education is moving to adopt the new American Association of Colleges of Nursing Essentials for Professional Nursing Education. As identified in two of the six domains of the essentials, graduates need to be prepared to address population health and utilize informatics and healthcare technologies. Community/public health nursing also has eight domains for generalist nurses linked to population health which will help prepare a skilled nursing workforce for the 21st century. The Institute for Healthcare Improvement's Triple Aim which evolved into the Quadruple Aim is focused on improving health outcomes within healthcare delivery. Through a literature review, a need for a Quadruple Aim model for nursing education was identified. Mirroring the Institute for Healthcare Improvement's Triple Aim for healthcare delivery, a Quadruple Aim for Nursing Education Model was developed. The model dimensions include (1) Population-focused Care, (2) Maximize Student Learning Experience, (3) Cost-effective Pedagogy, and (4) Nurse Educator Well-being. The Quadruple Aim for Nursing Education Model supports nursing education to prepare future nurses effectively and efficiently bridging population health concepts and issues with nursing informatics. Nurse educators are encouraged to utilize the model to transform nursing education.

Exposure to family and domestic violence is associated with lower attendance and higher suspension in school children.

BACKGROUND: Exposure to family and domestic violence (FDV) in childhood can have a detrimental effect on children's health and social outcomes. However, research on the school outcomes of children exposed to FDV is scant. OBJECTIVES: To investigate the impact of FDV exposure on school attendance and suspension in Aboriginal and non-Aboriginal children. METHODS: A population-based retrospective cohort study of school children, in grade 1 to 10, born from 1993 to 2006 in Western Australia (n = 26,743) using linked administrative data. Multivariate logistic regression analysis was used to calculate odds ratios and 95% confidence intervals to determine the association with school attendance and suspension outcomes for children exposed to FDV compared to non-exposed children. RESULTS: Compared to non-exposed children, children exposed to FDV have an increase of poor school attendance: Aboriginal children adjusted odds ratio (aOR) = 1.91, 95% confidence interval (CI): 1.75-2.07, non-Aboriginal children aOR = 2.42, 95%CI: 2.12-2.75. FDV-exposed children also have an increased risk of school suspension: Aboriginal children aOR = 1.60, 95%CI: 1.47-1.74, non-Aboriginal children aOR = 2.68, 95%CI: 2.35-3.05, compared to non-exposed counterparts. CONCLUSION: Exposure to FDV is associated with an increased odds of poor school attendance and school suspension. Evidence-based and innovative strategies are needed to support children who are exposed to FDV. This involves responding in ways that does not cause further trauma to children; a restorative and trauma-informed approach is vital.

Evolving beyond antiracism: Reflections on the experience of developing a cultural safety curriculum in a tertiary education setting.

There is an inextricable link between cultural and clinical safety. In Australia high-profile Aboriginal deaths in custody, publicised institutional racism in health services and the international Black Lives Matter movement have cemented momentum to ensure culturally safe care. However, racism within health professionals and health professional students remains a barrier to increasing the number of Aboriginal and Torres Strait Islander Health professionals. The Australian Health Practitioner Regulation Agency's Aboriginal and Torres Strait Islander Health Strategy's objective to 'eliminate racism from the health system', and the recent adoption of the Aboriginal and Torres Strait Islander peoples led cultural safety definition, has instigated systems level reflections on decolonising practice. This article explores cultural safety as the conceptual antithesis to racism, examining its origins, and contemporary evolution led by Aboriginal and Torres Strait Islander peoples in Australia, including its development in curriculum innovation. The application of cultural safety is explored using in-depth reflection, and the crucial development of integrating critical consciousness theory, as a precursor to culturally safe practice, is discussed. Novel approaches to university curriculum development are needed to facilitate culturally safe and decolonised learning and working environments, including the key considerations of non-Indigenous allyship and collaborative curriculum innovations and initiatives.

How does the school built environment impact students' bullying behaviour? A scoping review.

RATIONALE: School bullying is a public health concern affecting the physical and mental health of children and young people. While school-based interventions to prevent bullying have been developed internationally, the effectiveness of many interventions has been mixed and modest. Despite a growing recognition that the school built environment may impact bullying behaviour, few anti-bullying interventions have addressed the built environment. OBJECTIVE: This systematic scoping review explored existing literature for evidence that the school built environment influences bullying behaviour in school students. METHODS: The review was guided by Arksey and O'Malley's methodological framework for scoping reviews. A search of six databases (Medline, PsycINFO, ERIC, EMBASE, CINAHL Plus and The Cochrane Library) identified studies addressing primary, middle and secondary school students, bullying, school bullying locations, and school built environments. Peer-reviewed journal articles published in English prior to July 19, 2021, were included. RESULTS: In total, 7568 documents were screened by title and abstract. Following a full-text review, 61 studies (63 articles) were selected; 43 studies identified school bullying locations, and 19 studies linked features of the school built environment to bullying behaviour. Classrooms, playgrounds, and corridors were identified as common bullying locations. Features of the school built environment linked to bullying behaviour included security cameras, architectural design, aesthetics, seating, and vandalism. CONCLUSIONS: This review identified key school settings for anti-bullying interventions and identified gaps in existing built environment and bullying literature. Further analyses of published studies will inform anti-bullying policy and practice.

Pitavastatin Is Anti-Leukemic in a Bone Marrow Microenvironment Model of B-Lineage Acute Lymphoblastic Leukemia.

The lack of complete therapeutic success in the treatment of B-cell acute lymphoblastic leukemia (ALL) has been attributed, in part, to a subset of cells within the bone marrow microenvironment that are drug resistant. Recently, the cholesterol synthesis inhibitor, pitavastatin (PIT), was shown to be active in acute myeloid leukemia, prompting us to evaluate it in our in vitro co-culture model, which supports a chemo-resistant ALL population. We used phospho-protein profiling to evaluate the use of lipid metabolic active compounds in these chemo-resistant cells, due to the up-regulation of multiple active survival signals. In a co-culture with stromal cells, a shift towards anabolic processes occurred, which was further confirmed by assays showing increased lipid content. The treatment of REH leukemia cells with pitavastatin in the co-culture model resulted in significantly higher leukemic cell death than exposure to the standard-of-care chemotherapeutic agent, cytarabine (Ara-C). Our data demonstrates the use of pitavastatin as a possible alternative treatment strategy to improve patient outcomes in chemo-resistant, relapsed ALL.

Host type 2 immune response to xenogeneic serum components impairs biomaterial-directed osteo-regenerative therapies.

The transformative potential of cells as therapeutic agents is being realized in a wide range of applications, from regenerative medicine to cancer therapy to autoimmune disorders. The majority of these therapies require ex vivo expansion of the cellular product, often utilizing fetal bovine serum (FBS) in the culture media. However, the impact of residual FBS on immune responses to cell therapies and the resulting cell therapy outcomes remains unclear. Here, we show that hydrogel-delivered FBS elicits a robust type 2 immune response characterized by infiltration of eosinophils and CD4+ T cells. Host secretion of cytokines associated with type 2 immunity, including IL-4, IL-5, and IL-13, is also increased in FBS-containing hydrogels. We demonstrate that the immune response to xenogeneic serum components dominates the local environment and masks the immunomodulatory effects of biomaterial-delivered mesenchymal stromal/stem cells. Importantly, delivery of relatively small amounts of FBS (3.2% by volume) within BMP-2-containing biomaterial constructs dramatically reduces the ability of these constructs to promote de novo bone formation in a radial defect model in immunocompetent mice. These results urge caution when interpreting the immunological and tissue repair outcomes in immunocompetent pre-clinical models from cells and biomaterial constructs that have come in contact with xenogeneic serum components.

An International Research Collaborative to Examine Global Health Resilience Using the MyStrengths+MyHealth Application.

International organizations have called for the development of programs to strengthen global health resilience. This poster describes the development of an international research collaborative to examine whole-person health and resilience using the web-based application MyStrengths+MyHealth (MSMH). MSMH enables individuals to self-report strengths (resilience), challenges, and needs using simplified terms that have been community validated and at the fourth grade US reading level.

Hydrolytically Degradable Microgels with Tunable Mechanical Properties Modulate the Host Immune Response.

Hydrogel microparticles (microgels) are an attractive approach for therapeutic delivery because of their modularity, injectability, and enhanced integration with the host tissue. Multiple microgel fabrication strategies and chemistries have been implemented, yet manipulation of microgel degradability and its effect on in vivo tissue responses remains underexplored. Here, the authors report a facile method to synthesize microgels crosslinked with ester-containing junctions to afford tunable degradation kinetics. Monodisperse microgels of maleimide-functionalized poly(ethylene-glycol) are generated using droplet microfluidics crosslinked with thiol-terminated, ester-containing molecules. Tunable mechanics are achievable based on the ratio of degradable to nondegradable crosslinkers in the continuous phase. Degradation in an aqueous medium leads to microgel deformation based on swelling and a decrease in elastic modulus. Furthermore, degradation byproducts are cytocompatible and do not cause monocytic cell activation under noninflammatory conditions. These injectable microgels possess time-dependent degradation on the order of weeks in vivo. Lastly, the evaluation of tissue responses in a subcutaneous dorsal pocket shows a dynamic type-1 like immune response to the synthetic microgels, driven by interferon gamma (IFN-γ ) expression, which can be moderated by tuning the degradation properties. Collectively, this study demonstrates the development of a hydrolytic microgel platform that can be adapted to desired host tissue immune responses.

Towards an Evidence-Based Model of Workplace Postvention.

This instrumental case study explored what suicide postvention might offer workplaces using the example of a large metropolitan funeral company. A mixed methods approach was utilized to examine staff experiences with suicide bereavement funerals and responses to a bespoke postvention training package. Staff found funerals due to suicide difficult in terms of communication, engagement and emotionality. These challenges were commonly characterized by increased tension and concern. In the absence of a postvention informed approach, staff had developed individual ways to negotiate the identified challenges of this work. The introduction of a staff-informed postvention training package delivered improvements in staff confidence with communication, understanding and management of the impact of suicide bereavement, and increased willingness to share information about postvention services with families and mourners. The findings indicated that benefits of the training could be extended through organizational governance and integration of supports. The findings are used to inform a model of workplace postvention together with a methodology incorporating staff experience and organizational context.