Despite many years of research, cancer vaccines have largely been ineffective in the treatment of established cancers. Many barriers to immune-mediated destruction of malignant cells exist, and these ...likely limit the efficacy of cancer vaccines. In this study, we sought to enhance the efficacy of a cytomegalovirus (CMV)-based vaccine targeting melanoma by combining vaccination with other forms of immunotherapy. Adoptive cell therapy in humans and in animal models has been shown to be effective for tumor regression. Thus, in this study, we assessed whether CMV-based vaccines in combination with adoptively transferred antitumor T cells could provide greater antitumor protection than either therapy alone. Our results show that adoptive cell therapy greatly enhanced the antitumor effects of CMV-based vaccines targeting the foreign model antigen, OVA, or the melanoma differentiation antigen, gp100. Combination adoptive cell therapy and vaccination induced the upregulation of the inhibitory ligands, PD-L1, and Qa-1
, on B16 tumor cells. This expression paralleled the infiltration of tumors by vaccine-stimulated T cells which also expressed high levels of the receptors PD-1 and NKG2A/C/E, suggesting a potential mechanism of tumor immune evasion. Surprisingly, therapeutic blockade of the PD-1/PD-L1 and NKG2A/Qa-1
axes did not delay tumor growth following vaccination, suggesting that the presence of inhibitory ligands within malignant tissue may not be an effective biomarker for successful combination therapy with CMV-based vaccines. Overall, our studies show that therapeutic CMV-based vaccines in combination with adoptive T cell transfer alone are effective for tumor rejection.
Genetically engineered mouse models (GEMMs) help us to understand human pathologies and develop new therapies, yet faithfully recapitulating human diseases in mice is challenging. Advances in ...genomics have highlighted the importance of non-coding regulatory genome sequences, which control spatiotemporal gene expression patterns and splicing in many human diseases
. Including regulatory extensive genomic regions, which requires large-scale genome engineering, should enhance the quality of disease modelling. Existing methods set limits on the size and efficiency of DNA delivery, hampering the routine creation of highly informative models that we call genomically rewritten and tailored GEMMs (GREAT-GEMMs). Here we describe 'mammalian switching antibiotic resistance markers progressively for integration' (mSwAP-In), a method for efficient genome rewriting in mouse embryonic stem cells. We demonstrate the use of mSwAP-In for iterative genome rewriting of up to 115 kb of a tailored Trp53 locus, as well as for humanization of mice using 116 kb and 180 kb human ACE2 loci. The ACE2 model recapitulated human ACE2 expression patterns and splicing, and notably, presented milder symptoms when challenged with SARS-CoV-2 compared with the existing K18-hACE2 model, thus representing a more human-like model of infection. Finally, we demonstrated serial genome writing by humanizing mouse Tmprss2 biallelically in the ACE2 GREAT-GEMM, highlighting the versatility of mSwAP-In in genome writing.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused a global economic and health crisis. Recently, plasma levels of galectin-9 (Gal-9), a ...β-galactoside-binding lectin involved in immune regulation and viral immunopathogenesis, were reported to be elevated in the setting of severe COVID-19 disease. However, the impact of Gal-9 on SARS-CoV-2 infection and immunopathology remained to be elucidated. In this study, we demonstrate that Gal-9 treatment potently enhances SARS-CoV-2 replication in human airway epithelial cells (AECs), including immortalized AECs and primary AECs cultured at the air–liquid interface. Gal-9–glycan interactions promote SARS-CoV-2 attachment and entry into AECs in an angiotensin-converting enzyme 2 (ACE2)-dependent manner, enhancing the binding of the viral spike protein to ACE2. Transcriptomic analysis revealed that Gal-9 and SARS-CoV-2 infection synergistically induced the expression of key pro-inflammatory programs in AECs, including the IL-6, IL-8, IL-17, EIF2, and TNFα signaling pathways. Our findings suggest that manipulation of Gal-9 should be explored as a therapeutic strategy for SARS-CoV-2 infection.
AbstractObjectivesTo quantify mortality rates for patients successfully treated for hepatitis C in the era of interferon-free, direct acting antivirals and compare these rates with those of the ...general population.DesignPopulation based cohort study.SettingBritish Columbia, Scotland, and England (England cohort consists of patients with cirrhosis only).Participants21 790 people who were successfully treated for hepatitis C in the era of interferon-free antivirals (2014-19). Participants were divided into three liver disease severity groups: people without cirrhosis (pre-cirrhosis), those with compensated cirrhosis, and those with end stage liver disease. Follow-up started 12 weeks after antiviral treatment completion and ended on date of death or 31 December 2019.Main outcome measuresCrude and age-sex standardised mortality rates, and standardised mortality ratio comparing the number of deaths with that of the general population, adjusting for age, sex, and year. Poisson regression was used to identify factors associated with all cause mortality rates.Results1572 (7%) participants died during follow-up. The leading causes of death were drug related mortality (n=383, 24%), liver failure (n=286, 18%), and liver cancer (n=250, 16%). Crude all cause mortality rates (deaths per 1000 person years) were 31.4 (95% confidence interval 29.3 to 33.7), 22.7 (20.7 to 25.0), and 39.6 (35.4 to 44.3) for cohorts from British Columbia, Scotland, and England, respectively. All cause mortality was considerably higher than the rate for the general population across all disease severity groups and settings; for example, all cause mortality was three times higher among people without cirrhosis in British Columbia (standardised mortality ratio 2.96, 95% confidence interval 2.71 to 3.23; P<0.001) and more than 10 times higher for patients with end stage liver disease in British Columbia (13.61, 11.94 to 15.49; P<0.001). In regression analyses, older age, recent substance misuse, alcohol misuse, and comorbidities were associated with higher mortality rates.ConclusionMortality rates among people successfully treated for hepatitis C in the era of interferon-free, direct acting antivirals are high compared with the general population. Drug and liver related causes of death were the main drivers of excess mortality. These findings highlight the need for continued support and follow-up after successful treatment for hepatitis C to maximise the impact of direct acting antivirals.
Stromal and immune cells in the tumor microenvironment (TME) have been shown to directly affect high-grade serous ovarian cancer (HGSC) malignant phenotypes, however, how these cells interact to ...influence HGSC patients' survival remains largely unknown. To investigate the cell-cell communication in such a complex TME, we developed a SpatioImageOmics (SIO) pipeline that combines imaging mass cytometry (IMC), location-specific transcriptomics, and deep learning to identify the distribution of various stromal, tumor and immune cells as well as their spatial relationship in TME. The SIO pipeline automatically and accurately segments cells and extracts salient cellular features to identify biomarkers, and multiple nearest-neighbor interactions among tumor, immune, and stromal cells that coordinate to influence overall survival rates in HGSC patients. In addition, SIO integrates IMC data with microdissected tumor and stromal transcriptomes from the same patients to identify novel signaling networks, which would lead to the discovery of novel survival rate-modulating mechanisms in HGSC patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Neuronal loss is a common component of a variety of neurodegenerative disorders (including Alzheimer's, Parkinson's, and Huntington's disease) and brain traumas (stroke, epilepsy, and traumatic brain ...injury). One brain region that commonly exhibits neuronal loss in several neurodegenerative disorders is the hippocampus, an area of the brain critical for the formation and retrieval of memories. Long-lasting and sometimes unrecoverable deficits caused by neuronal loss present a unique challenge for clinicians and for researchers who attempt to model these traumas in animals. Can these deficits be recovered, and if so, is the brain capable of regeneration following neuronal loss? To address this significant question, we utilized the innovative CaM/Tet-DT(A) mouse model that selectively induces neuronal ablation. We found that we are able to inflict a consistent and significant lesion to the hippocampus, resulting in hippocampally-dependent behavioral deficits and a long-lasting upregulation in neurogenesis, suggesting that this process might be a critical part of hippocampal recovery. In addition, we provide novel evidence of angiogenic and vasculature changes following hippocampal neuronal loss in CaM/Tet-DTA mice. We posit that angiogenesis may be an important factor that promotes neurogenic upregulation following hippocampal neuronal loss, and both factors, angiogenesis and neurogenesis, can contribute to the adaptive response of the brain for behavioral recovery.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alzheimer disease is characterized by the accumulation of β-amyloid (Aβ) plaques and tau-laden neurofibrillary tangles. Emerging studies suggest that in neurodegenerative diseases, aggregation of one ...protein species can promote other proteinopathies and that inflammation plays an important role in this process. To study the interplay between Aβ deposition, tau pathology, and microgliosis, we established a new AD transgenic mouse model by crossing 5xfAD mice with Thy-Tau22 transgenic mice. The resulting 'T5x' mice exhibit a greater than three-fold increase in misfolded and hyperphosphorylated tau and further substantiates the hypothesis that Aβ accelerates tau pathology. Surprisingly, T5x mice exhibit a 40-50 % reduction in Aβ plaque load and insoluble Aβ species when compared with aged-matched 5xfAD littermates. T5x mice exhibit significant changes in cytokine production, an almost doubling of microglial number, and a dramatic shift in microglia activation state. Furthermore, T5x microglia exhibit increased phagocytic capacity that enhances the clearance of insoluble Aβ and decreasing plaque load. Therefore, our results suggest that strategies to increase the phagocytic ability of microglia can be employed to reduce Aβ and that tau-induced changes in microglial activation state can promote the clearance of Aβ.
Aim
To examine the mediating effect of coping strategies on the consequences of nursing and non‐nursing (administrative) stressors on the job satisfaction of nurses during change management.
...Background
Organisational change can result in an increase in nursing and non‐nursing‐related stressors, which can have a negative impact on the job satisfaction of nurses employed in health‐care organisations.
Method
Matched data were collected in 2009 via an online survey at two time‐points (six months apart).
Results
Partial least squares path analysis revealed a significant causal relationship between Time 1 administrative and role stressors and an increase in nursing‐specific stressors in Time 2. A significant relationship was also identified between job‐specific nursing stressors and the adoption of effective coping strategies to deal with increased levels of change‐induced stress and strain and the likelihood of reporting higher levels of job satisfaction in Time 2.
Conclusions
The effectiveness of coping strategies is critical in helping nurses to deal with the negative consequences of organisational change.
Implications for nursing management
This study shows that there is a causal relationship between change, non‐nursing stressors and job satisfaction. Senior management should implement strategies aimed at reducing nursing and non‐nursing stress during change in order to enhance the job satisfaction of nurses.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK, VSZLJ
Highlights • Repeated spatial training improves cognitive performance in 3xTg-AD mice. • Repetitive MWM training improves cognition in other hippocampal spatial tasks. • Repetitive MWM training ...mitigate cognitive deficits in a cortical memory test.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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