Infection by human cytomegalovirus (HCMV) leads to NKG2C-driven expansion of adaptive natural killer (NK) cells, contributing to host defense. However, approximately 4% of all humans carry a ...homozygous deletion of the gene that encodes NKG2C (NKG2C−/−). Assessment of NK cell repertoires in 60 NKG2C−/− donors revealed a broad range of NK cell populations displaying characteristic footprints of adaptive NK cells, including a terminally differentiated phenotype, functional reprogramming, and epigenetic remodeling of the interferon (IFN)-γ promoter. We found that both NKG2C− and NKG2C+ adaptive NK cells expressed high levels of CD2, which synergistically enhanced ERK and S6RP phosphorylation following CD16 ligation. Notably, CD2 co-stimulation was critical for the ability of adaptive NK cells to respond to antibody-coated target cells. These results reveal an unexpected redundancy in the human NK cell response to HCMV and suggest that CD2 provides “signal 2” in antibody-driven adaptive NK cell responses.
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•NKG2C−/− donors have normal T cell immunity to cytomegalovirus•NKG2C−/− donors have normal frequencies of adaptive NK cells•CD2 is critical for antibody-triggered responses by adaptive NK cells•CD2 synergizes with NKG2C in classical adaptive NK cells
Liu et al. demonstrate the emergence of redundant adaptive NK cell subsets in NKG2C−/− donors. Functional studies unraveled a critical role for CD2 in antibody-dependent responses by adaptive NK cells, paving the way for new strategies to harness their cytotoxic potential in cell therapy.
•Prescribed opioid-based pain reliever use was examined.•Compared groups include individuals with and without mood and/or anxiety disorders.•Mood and/or anxiety disorder was associated with ...prescribed opioid use.•Mood and/or anxiety disorders may be modifiable risk factors for opioid use.
In the context of the ongoing North American overdose crisis, a clear understanding of opioid prescription and usage trends is important. Although individuals with mood and/or anxiety disorders are a sub-population at increased risk of developing substance use disorders, they have been identified as more likely to receive opioid prescriptions. The primary objective of this study was to investigate differences in prescribed opioid-based pain reliever use between Canadians with and without diagnosed mood and/or anxiety disorders.
We utilized data from the 2015-2016 Canadian Community Health Survey (CCHS), a population-based, cross-sectional survey. We examined self-reported diagnoses of mood and/or anxiety disorders and self-reported prescribed opioid-based pain reliever use. Logistic regression modeling was used to estimate the unadjusted and adjusted odds of prescribed opioid-based pain reliever use associated with mood and/or anxiety disorders.
Our study sample had 2,810 individuals. The prevalence of mood and/or anxiety disorders and prescribed opioid use was 11.7% and 14.6%, respectively. Individuals diagnosed with mood and/or anxiety disorders were more likely to use prescribed opioid-based pain relievers compared with individuals without these diagnoses (OR = 2.36, 95% CI = 1.64, 3.41), even after adjustment for age, sex, total household income, cultural/racial background, and chronic pain (AOR= 1.78, 95% CI= 1.23, 2.58).
Our findings suggest that mood and/or anxiety disorders were positively associated with prescribed opioid-based pain reliever use. Future research should investigate potential unmet healthcare needs among individuals with these conditions, as mood and/or anxiety disorders may be modifiable risk factors.
Based on recent advances in organoid research as well as the need to find more accurate models for drug screening in cancer research, patient-derived organoids have emerged as an effective in vitro ...model system to study cancer. Showing numerous advantages over 2D cell lines, 3D cell lines, and primary cell culture, organoids have been applied in drug screening to demonstrate the correlation between genetic mutations and sensitivity to targeted therapy. Organoids have also been used in co-clinical trials to compare drug responses in organoids to clinical responses in the corresponding patients. Numerous studies have reported the successful use of organoids to predict therapy response in cancer patients. Recently, organoids have been adopted to predict treatment response to radiotherapy and immunotherapy. The development of high throughput drug screening and organoids-on-a-chip technology can advance the use of patient-derived organoids in clinical practice and facilitate therapeutic decision-making.
Human natural killer (NK) cells are functionally regulated by killer cell immunoglobulin-like receptors (KIRs) and their interactions with HLA class I molecules. As KIR expression in a given NK cell ...is genetically hard-wired, we hypothesized that KIR repertoire perturbations reflect expansions of unique NK-cell subsets and may be used to trace adaptation of the NK-cell compartment to virus infections. By determining the human “KIR-ome” at a single-cell level in more than 200 donors, we were able to analyze the magnitude of NK cell adaptation to virus infections in healthy individuals. Strikingly, infection with human cytomegalovirus (CMV), but not with other common herpesviruses, induced expansion and differentiation of KIR-expressing NK cells, visible as stable imprints in the repertoire. Education by inhibitory KIRs promoted the clonal-like expansion of NK cells, causing a bias for self-specific inhibitory KIRs. Furthermore, our data revealed a unique contribution of activating KIRs (KIR2DS4, KIR2DS2, or KIR3DS1), in addition to NKG2C, in the expansion of human NK cells. These results provide new insight into the diversity of KIR repertoire and its adaptation to virus infection, suggesting a role for both activating and inhibitory KIRs in immunity to CMV infection.
•Clonal-like expansion of NK cells in response to CMV infection causes stable imprints in the human KIR repertoire.•Education by inhibitory KIRs promotes the expansion of NK cells, causing repertoire skewing and a bias for self-specific inhibitory KIRs.
Introduction
Many health providers and communicators who are concerned that patients will not understand numbers instead use verbal probabilities (e.g., terms such as “rare” or “common”) to convey ...the gist of a health message.
Objective
To assess patient interpretation of and preferences for verbal probability information in health contexts.
Methods
We conducted a systematic review of literature published through September 2020. Original studies conducted in English with samples representative of lay populations were included if they assessed health-related information and elicited either (a) numerical estimates of verbal probability terms or (b) preferences for verbal vs. quantitative risk information.
Results
We identified 33 original studies that referenced 145 verbal probability terms, 45 of which were included in at least two studies and 19 in three or more. Numerical interpretations of each verbal term were extremely variable. For example, average interpretations of the term “rare” ranged from 7 to 21%, and for “common,” the range was 34 to 71%. In a subset of 9 studies, lay estimates of verbal probability terms were far higher than the standard interpretations established by the European Commission for drug labels. In 10 of 12 samples where preferences were elicited, most participants preferred numerical information, alone or in combination with verbal labels.
Conclusion
Numerical interpretation of verbal probabilities is extremely variable and does not correspond well to the numerical probabilities established by expert panels. Most patients appear to prefer quantitative risk information, alone or in combination with verbal labels. Health professionals should be aware that avoiding numeric information to describe risks may not match patient preferences, and that patients interpret verbal risk terms in a highly variable way.
Protein arginine methyltransferases (PRMTs) play important roles in protein methylation. PRMT5 is the major type II arginine methyltransferase that catalyzes the transfer of two methyl groups ...symmetrically to the arginine residues of either histone or non-histone proteins. In recent years, increasing evidence has shown that PRMT5, as an oncogene, plays an indispensable regulatory role in the pathological progression of several human cancers by promoting the proliferation, invasion, and migration of cancer cells. PRMT5 is overexpressed in many malignant tumors and plays an important role in the occurrence and development of cancer, which suggests that PRMT5 may become a potential biomarker or therapeutic target of cancer. This article reviews the biological function, mechanism, and clinical significance of PRMT5 in tumorigenesis.
Immune checkpoint inhibitors (ICIs) are linked to diverse immune-related adverse events (irAEs). Rare irAEs surface first in clinical practice. Here, we systematically studied the rare irAE, ...cytokine-release syndrome (CRS), in a cohort of 2672 patients treated with ICIs at Karolinska University Hospital in Stockholm, Sweden. We find that the risk of ICI-induced CRS - defined as fever, negative microbiological findings and absence of other probable causes within 30 days after ICI treatment - is approximately 1%, higher than previously reported. ICI-induced CRS was often mild and rechallenge with ICIs after mild CRS was generally safe. However, two out of 28 patients experienced high-grade CRS, and one was fatal. While C-reactive protein (CRP) and procalcitonin were not discriminative of fatal CRS, our data suggest that the quick Sequential Organ Failure Assessment (qSOFA) score might identify high-risk patients. These data provide a framework for CRS risk assessment and motivate multicenter studies to improve early CRS diagnosis.Immune checkpoint inhibitors (ICIs) are linked to diverse immune-related adverse events (irAEs). Rare irAEs surface first in clinical practice. Here, we systematically studied the rare irAE, cytokine-release syndrome (CRS), in a cohort of 2672 patients treated with ICIs at Karolinska University Hospital in Stockholm, Sweden. We find that the risk of ICI-induced CRS - defined as fever, negative microbiological findings and absence of other probable causes within 30 days after ICI treatment - is approximately 1%, higher than previously reported. ICI-induced CRS was often mild and rechallenge with ICIs after mild CRS was generally safe. However, two out of 28 patients experienced high-grade CRS, and one was fatal. While C-reactive protein (CRP) and procalcitonin were not discriminative of fatal CRS, our data suggest that the quick Sequential Organ Failure Assessment (qSOFA) score might identify high-risk patients. These data provide a framework for CRS risk assessment and motivate multicenter studies to improve early CRS diagnosis.
Here, we present FissionNet, a proteome-wide binary protein interactome for S. pombe, comprising 2,278 high-quality interactions, of which ∼50% were previously not reported in any species. FissionNet ...unravels previously unreported interactions implicated in processes such as gene silencing and pre-mRNA splicing. We developed a rigorous network comparison framework that accounts for assay sensitivity and specificity, revealing extensive species-specific network rewiring between fission yeast, budding yeast, and human. Surprisingly, although genes are better conserved between the yeasts, S. pombe interactions are significantly better conserved in human than in S. cerevisiae. Our framework also reveals that different modes of gene duplication influence the extent to which paralogous proteins are functionally repurposed. Finally, cross-species interactome mapping demonstrates that coevolution of interacting proteins is remarkably prevalent, a result with important implications for studying human disease in model organisms. Overall, FissionNet is a valuable resource for understanding protein functions and their evolution.
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•A proteome-wide network of 2,278 high-quality binary S. pombe protein interactions•Species-specific interaction rewiring among yeasts and human•Gene duplication modes shape the functional fate of paralogous proteins•Cross-species interactome mapping uncovers extensive coevolution
FissionNet is a proteome-wide binary interactome network for S. pombe. Comparative analyses of FissionNet with protein networks in budding yeast and human reveal how protein networks evolve, principles of gene repurposing following duplication, and insights into species-specific alterations of function.
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