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Background Immune checkpoint protein V-domain immunoglobulin suppressor of T cell activation (VISTA) controls antitumor immunity and is a valuable target for cancer immunotherapy. Previous mechanistic studies have indicated that VISTA impairs the toll-like receptor (TLR)-mediated activation of myeloid antigen-presenting cells, promoting the expansion of myeloid-derived suppressor cells, and suppressing tumor-reactive cytotoxic T cell function.Methods The aim of this study was to develop a dual-action lipid nanoparticle (dual-LNP) coloaded with VISTA-specific siRNA and TLR9 agonist CpG oligonucleotide. We used three murine preclinical tumor models, melanoma YUMM1.7, melanoma B16F10, and colon carcinoma MC38 to assess the functional synergy of the two cargoes of the dual LNP and therapeutic efficacy.Results The dual-LNP synergistically augmented antitumor immune responses and rejected large established tumors whereas LNPs containing VISTA siRNA or CpG alone were ineffective. In comparison with therapies using the soluble CpG and a VISTA-specific monoclonal antibody, the dual-LNP demonstrated superior therapeutic efficacy yet with reduced systemic inflammatory cytokine production. In three murine models, the dual-LNP treatment achieved a high cure rate. Tumor rejection was associated with influx of immune cells to tumor tissues, augmented dendritic cell activation, production of proinflammatory cytokines, and improved function of cytotoxic T cells.Conclusions Our studies show the dual-LNP ensured codelivery of its synergistic cargoes to tumor-infiltrating myeloid cells, leading to simultaneous silencing of VISTA and stimulation of TLR9. As a result, the dual-LNP drove a highly potent antitumor immune response that rejected large aggressive tumors, thus may be a promising therapeutic platform for treating immune-cold tumors.

Summary: Myeloid-derived suppressor cells (MDSCs) impair antitumor immune responses. Identifying regulatory circuits during MDSC development may bring new opportunities for therapeutic interventions. We report that the V-domain suppressor of T cell activation (VISTA) functions as a key enabler of MDSC differentiation. VISTA deficiency reduced STAT3 activation and STAT3-dependent production of polyamines, which causally impaired mitochondrial respiration and MDSC expansion. In both mixed bone marrow (BM) chimera mice and myeloid-specific VISTA conditional knockout mice, VISTA deficiency significantly reduced tumor-associated MDSCs but expanded monocyte-derived dendritic cells (DCs) and enhanced T cell-mediated tumor control. Correlated expression of VISTA and arginase-1 (ARG1), a key enzyme supporting polyamine biosynthesis, was observed in multiple human cancer types. In human endometrial cancer, co-expression of VISTA and ARG1 on tumor-associated myeloid cells is associated with poor survival. Taken together, these findings unveil the VISTA/polyamine axis as a central regulator of MDSC differentiation and warrant therapeutically targeting this axis for cancer immunotherapy.

The differentiation, survival, and effector function of tumor-specific CD8+ cytotoxic T cells lie at the center of antitumor immunity. Due to the lack of proper costimulation and the abundant immunosuppressive mechanisms, tumor-specific T cells show a lack of persistence and exhausted and dysfunctional phenotypes. Multiple coinhibitory receptors, such as PD-1, CTLA-4, VISTA, TIGIT, TIM-3, and LAG-3, contribute to dysfunctional CTLs and failed antitumor immunity. These coinhibitory receptors are collectively called immune checkpoint receptors (ICRs). Immune checkpoint inhibitors (ICIs) targeting these ICRs have become the cornerstone for cancer immunotherapy as they have established new clinical paradigms for an expanding range of previously untreatable cancers. Given the nonredundant yet convergent molecular pathways mediated by various ICRs, combinatorial immunotherapies are being tested to bring synergistic benefits to patients. In this review, we summarize the mechanisms of several emerging ICRs, including VISTA, TIGIT, TIM-3, and LAG-3, and the preclinical and clinical data supporting combinatorial strategies to improve existing ICI therapies.

Abstract Background During pregnancy asthma may remain stable, improve or worsen. The factors underlying the deleterious effect of pregnancy on asthma remain unknown. Oxytocin is a neurohypophyseal protein that regulates a number of central and peripheral responses such as uterine contractions and milk ejection. Additional evidence suggests that oxytocin regulates inflammatory processes in other tissues given the ubiquitous expression of the oxytocin receptor. The purpose of this study was to define the role of oxytocin in modulating human airway smooth muscle (HASMCs) function in the presence and absence of IL-13 and TNFα, cytokines known to be important in asthma. Method Expression of oxytocin receptor in cultured HASMCs was performed by real time PCR and flow cytomery assays. Responses to oxytocin was assessed by fluorimetry to detect calcium signals while isolated tracheal rings and precision cut lung slices (PCLS) were used to measure contractile responses. Finally, ELISA was used to compare oxytocin levels in the bronchoalveloar lavage (BAL) samples from healthy subjects and those with asthma. Results PCR analysis demonstrates that OXTR is expressed in HASMCs under basal conditions and that both interleukin (IL)-13 and tumor necrosis factor (TNFα) stimulate a time-dependent increase in OXTR expression at 6 and 18 hr. Additionally, oxytocin increases cytosolic calcium levels in fura-2-loaded HASMCs that were enhanced in cells treated for 24 hr with IL-13. Interestingly, TNFα had little effect on oxytocin-induced calcium response despite increasing receptor expression. Using isolated murine tracheal rings and PCLS, oxytocin also promoted force generation and airway narrowing. Further, oxytocin levels are detectable in bronchoalveolar lavage (BAL) fluid derived from healthy subjects as well as from those with asthma. Conclusion Taken together, we show that cytokines modulate the expression of functional oxytocin receptors in HASMCs suggesting a potential role for inflammation-induced changes in oxytocin receptor signaling in the regulation of airway hyper-responsiveness in asthma.

Interventions addressing cognitive and emotional difficulties after acquired brain injury (ABI) often focus on specific impairments in cognition or mood. These interventions can be effective at addressing their specific target, but do not routinely translate to improved activity and participation outcomes. Approaches that combine cognitive and psychological rehabilitation are increasingly popular; however, to date, there have been no systematic evaluations of their efficacy. We conducted a systematic review of five databases, searching for randomised controlled trials of adults with diagnoses of non-progressive ABI at least 1-month post injury, in receipt of interventions that combined cognitive and psychological components compared to any control. Screening and data extraction were evaluated by two independent reviewers using a standardised protocol. Effect sizes were calculated using Hedge's g and estimated using a random-effects model. Risk of bias was assessed using the PEDro-P rating system, and quality of evidence evaluated using the grading of recommendation, assessment, development and evaluation (GRADE) approach. Thirteen studies were included in the meta-analysis (n = 684). There was an overall small-to-medium effect (g = 0.42) for combined interventions compared with controls, with gains maintained at 6-month follow-up. Improvements were observed at the level of impairment, activity, participation and quality of life. GRADE ratings and analyses investigating sensitivity, heterogeneity and publication bias indicated that these effects were robust. No a priori variables moderated these effects. Overall, this review provides strong evidence that combined cognitive and psychological interventions create meaningful change in the lives of people with ABI. [ABSTRACT FROM AUTHOR]

Introduction: This study explores the motivators to use learning management systems (LMS) adopted and used in eLearning by Hong Kong universities among Mainland Chinese postgraduate students amid COVID-19 pandemic. Methods: An adapted and extended UTUAT2 model was first proposed and tested using the structural equation modeling approach. Through self-report online questionnaire, data were collected in 2022 from 352 Mainland Chinese postgraduate students of nine universities in Hong Kong. The reliability and validity of the data were tested using the confirmatory factor analysis, followed by path analysis to test the hypotheses in the proposed model. Results: The study revealed nine motivators which explained 50% of the variance in LMS use intention. Trust (0.204), instructor characteristics (0.202), performance expectancy (0.181), and facilitating conditions (0.181) were identified as strong motivators of behavioral intention. Other factors such as effort expectancy (0.148), learning value (0.118) and social influence (0.115) also had significant positive effects on LMS use intention. Habit (0.014) and hedonic motivation (-0.016) had no significant direct effect on it. Discussion: These findings provide inspirations for educational stakeholders to promote the acceptance of LMS platforms among distance and online learners who adopt the cyberspace as the only means of learning. They also offer insights about instructor recruitment and evaluation methods. [ABSTRACT FROM AUTHOR]

Introduction: Closed hand fractures represent a significant proportion of emergency department attendances, result in substantial health service utilisation and have a detrimental effect on quality of life. Increasingly, hand therapists in the United Kingdom provide first line fracture treatment. However, the knowledge and skills required to work in such an extended scope capacity have not been elucidated or standardised. This literature review synthesises and reports evidence for the knowledge requisite of clinicians to make evidence-based treatment decisions for patients with hand fractures. Methods: A systematic search was undertaken, using Embase, MEDLINE, PsychInfo and CINAHL electronic databases. Inclusion criteria were English language, full research reports of studies assessing of the reliability or validity of the decision-making process in hand fracture treatment published between 2013 and 2023. Data were summarised narratively. Results: 15 studies met inclusion criteria; most assessed decision making for metacarpal fractures. Studies on imaging (n = 4) suggested the reliability of plain radiograph interpretation of hand fracture characteristics such as angulation is good and similar across various levels of experience. Agreement between surgeons and therapists in choosing surgical or nonsurgical treatment was generally good, but factors influencing decision making remained unclear. No evidence was identified that explored clinical assessment knowledge (subjective or objective patient factors) or the specific competencies required to treat hand fractures. Conclusions: There is limited evidence for the knowledge and skills required of clinicians for the competent assessment and treatment of hand fractures. Stakeholder consensus work is required to develop robust competencies and standardise practice. [ABSTRACT FROM AUTHOR]

A novel brain-targeted and reactive oxygen species-activatable manganese dioxide containing nanoparticle system functionalized with anti-amyloid-β antibody (named aAβ-BTRA-NC) developed by our group has shown great promise as a highly selective magnetic resonance imaging (MRI) contrast agent for early detection and multitargeted disease-modifying treatment of Alzheimer's disease (AD). To further evaluate the suitability of the formulation for future clinical application, we investigated the safety, biodistribution, and pharmacokinetic profile of aAβ-BTRA-NC in a transgenic TgCRND8 mouse AD model, wild type (WT) littermate, and CD-1 mice. Dose-ascending studies demonstrated that aAβ-BTRA-NC was well-tolerated by the animals up to 300 μmol Mn/kg body weight [b.w.], 3 times the efficacious dose for early AD detection without apparent adverse effects; Histopathological, hematological, and biochemical analyses indicated that a single dose of aAβ-BTRA-NC did not cause any toxicity in major organs. Immunotoxicity data showed that aAβ-BTRA-NC was safer than commercially available gadolinium-based MRI contrast agents at an equivalent dose of 100 μmol/kg b.w. of metal ions. Intravenously administered aAβ-BTRA-NC was taken up by main organs with the order of liver, kidneys, intestines, spleen, followed by other organs, and cleared after one day to one week post injection. Pharmacokinetic analysis indicated that the plasma concentration profile of aAβ-BTRA-NC followed a 2-compartmental model with faster clearance in the AD mice than in the WT mice. The results suggest that aAβ-BTRA-NC exhibits a strong safety profile as a nanotheranostic agent which warrants more robust preclinical development for future clinical applications. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockade is a promising approach to activate antitumor immunity and improve the survival of patients with cancer. V-domain immunoglobulin suppressor of T cell activation (VISTA) is an immune checkpoint target; however, the downstream signaling mechanisms are elusive. Here, we identify leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) as a VISTA binding partner, which acts as an inhibitory receptor by engaging VISTA and suppressing T cell receptor signaling pathways. Mice with T cell–specific LRIG1 deletion developed superior antitumor responses because of expansion of tumor-specific cytotoxic T lymphocytes (CTLs) with increased effector function and survival. Sustained tumor control was associated with a reduction of quiescent CTLs (TCF1+ CD62Lhi PD-1low) and a reciprocal increase in progenitor and memory-like CTLs (TCF1+ PD-1+). In patients with melanoma, elevated LRIG1 expression on tumor-infiltrating CD8+ CTLs correlated with resistance to immunotherapies. These results delineate the role of LRIG1 as an inhibitory immune checkpoint receptor and propose a rationale for targeting the VISTA/LRIG1 axis for cancer immunotherapy. Editor's summary: The negative checkpoint regulator VISTA has emerged as a promising target for cancer immunotherapy. VISTA plays an important role in maintaining T cell quiescence; however, the molecular mechanisms through which VISTA regulates antitumor immunity are not well defined. In this study, Ta et al. identified LRIG1 as a VISTA-binding partner and co-inhibitory receptor. VISTA engagement by LRIG1 impaired murine antitumor immunity by promoting quiescence in tumor-specific CD8 T cells and limited the abundance of progenitor and memory-like cells with the ability to differentiate into effector T cells. In patients with melanoma, expression of LRIG1 on tumor-infiltrating lymphocytes correlated with resistance to immunotherapy. Together, these findings suggest that selectively inhibiting VISTA/LRIG1 may be an effective cancer immunotherapy. —Hannah Isles [ABSTRACT FROM AUTHOR]

PURPOSE: BMT CTN 1102 was a phase III trial comparing reduced-intensity allogeneic hematopoietic cell transplantation (RIC alloHCT) to standard of care for persons with intermediate- or high-risk myelodysplastic syndrome (MDS). We report results of a cost-effectiveness analysis conducted alongside the clinical trial. METHODS: Three hundred eighty-four patients received HCT (n = 260) or standard of care (n = 124) according to availability of a human leukocyte antigen–matched donor. Cost-effectiveness was calculated from US commercial and Medicare perspectives over a 20-year time horizon. Health care utilization and costs were estimated using propensity score–matched cohorts of HCT recipients in the OptumLabs Data Warehouse (age 50-64 years) and Medicare (age 65 years and older). EuroQol 5 Dimension (EQ-5D) surveys of trial participants were used to derive health state utilities. RESULTS: Extrapolated 20-year overall survival for those age 50-64 years was 29% for HCT (n = 105) versus 13% for usual care (n = 44) and 31% for HCT (n = 155) versus 12% for non-HCT (n = 80) for those age 65 years and older. HCT was more effective (+2.36 quality-adjusted life-years [QALYs] for age 50-64 years and +2.92 QALYs for age 65 years and older) and more costly (+$452,242 in US dollars (USD) for age 50-64 years and +$233,214 USD for age 65 years and older) than usual care, with incremental cost-effectiveness ratios of $191,487 (USD)/QALY and $79,834 (USD)/QALY, respectively. For persons age 50-64 years, there was a 29% chance that HCT was cost-effective using a willingness-to-pay (WTP) threshold of $150K (USD)/QALY and 51% at a $200K (USD)/QALY. For persons age 65 years and older, the probability was 100% at a WTP >$150K (USD)/QALY. CONCLUSION: Among patients age 65 years and older with high-risk MDS, RIC HCT is a high-value strategy. For those age 50-64 years, HCT is a lower-value strategy but has similar cost-effectiveness to other therapies commonly used in oncology. For patients with high-risk myelodysplastic syndrome, bone marrow transplant is a cost-effective therapy option. [ABSTRACT FROM AUTHOR]

In this study, we employ a dual-objective optimization model, utilizing the Implicit Modified Coverage Location Problem (MCLP-Implicit) approach, to determine an appropriate fire station allocation. Our objectives encompass maximizing coverage in areas with a heightened projected demand, based on socioeconomic predictors of building fires, and concurrently minimizing the distance of uncovered demand zones to the closest fire station. The challenges of this model reflect the criticality of strategic placement, aiming for not just swift response times but also the complete coverage of a region with priority given to subregions with a pronounced potential for incidents. The applicability of the proposed approach is demonstrated through a case study in south-east Queensland. Our findings indicate that there is a tangible justification for adopting this model. The broader coverage and wider spread of locations it produces can greatly aid in the dynamic deployment of personnel during surges caused by seasonal fluctuations or unforeseen calamities. By weaving in socioeconomic aspects into demand predictions, our model has also maintained appropriate coverage to socioeconomically disadvantaged communities in the region. Nevertheless, it is paramount to underline the recommendation that further research should account for road connectivity—a pivotal factor when pinpointing these locations in the real world. This research paves the way for enriched insights in long-term urban planning and fire response protocol crafting, especially in regions mirroring similar socioeconomic profiles or risks of natural disasters, not to mention its commercial implications to the relevant industry servicing the fire and rescue authorities. [ABSTRACT FROM AUTHOR]

Objective: A scoping review of studies published in the first year of the COVID-19 pandemic focused on individuals with pre-existing symptoms of depression, anxiety, and specified stressor-related disorders, with the objective of mapping the research conducted. Eligibility criteria: (1) direct study of individuals with pre-existing depressive, anxiety, and/or specified stressor-related (i.e., posttraumatic stress, acute stress) disorders/issues; (2) focus on mental health-related pandemic effects, and; (3) direct study of mental health symptoms related to depression, anxiety, or psychological distress. Sources of evidence: Database-specific subject headings and natural language keywords were searched in Medline, Embase, APA PsycInfo, and Cumulative Index to Nursing & Allied Health Literature (CINAHL) up to March 3, 2021. Review of potentially relevant studies was conducted by two independent reviewers and proceeded in two stages: (1) title and abstract review, and; (2) full paper review. Data charting: Study details (i.e., location, design and methodology, sample or population, outcome measures, and key findings) were extracted from included studies by one reviewer and confirmed by the Principal Investigator. Results: 66 relevant articles from 26 countries were identified. Most studies adopted a cross-sectional design and were conducted via online survey. About half relied on general population samples, with the remainder assessing special populations, primarily mental health patients. The most commonly reported pre-existing category of disorders or symptoms was depression, followed closely by anxiety. Most studies included depressive and anxiety symptoms as outcome measures and demonstrated increased vulnerability to mental health symptoms among individuals with a pre-existing mental health issue. Conclusion: These findings suggest that improved mental health supports are needed during the pandemic and point to future research needs, including reviews of other diagnostic categories and reviews of research published in subsequent years of the pandemic. [ABSTRACT FROM AUTHOR]