BackgroundWith the growing recognition that patients and partners react to a cancer diagnosis as an interdependent system and increasing evidence that psychosocial interventions can be beneficial to both patients and partners, there has been a recent increase in the attention given to interventions that target couples. The aim of this systematic review was to identify existing couple-based interventions for patients with cancer and their partners and explore the efficacy of these interventions (including whether there is added value to target the couple versus individuals), the content and delivery of couple-based interventions, and to identify the key elements of couple-based interventions that promote improvement in adjustment to cancer diagnosis.MethodA systematic review of the cancer literature was performed to identify experimental and quasi-experimental couple-based interventions published between 1990 and 2011. To be considered for this review, studies had to test the efficacy of a psychosocial intervention for couples affected by cancer. Studies were excluded if they were published in a language other than English or French, focused on pharmacological, exercise, or dietary components combined with psychosocial components, or did not assess the impact of the intervention on psychological distress (e.g., depression, anxiety) or quality of life. Data were extracted using a standardised data collection form, and were analysed independently by three reviewers.ResultsOf the 709 articles screened, 23 were included in this review. Couple-based interventions were most efficacious in improving couple communication, psychological distress, and relationship functioning. Interventions had a limited impact on physical distress and social adjustment. Most interventions focused on improving communication and increasing understanding of the cancer diagnosis within couples. Interventions were most often delivered by masters-level nurses or clinical psychologists. Although most were delivered in person, few were telephone-based. No difference in efficacy was noted based on mode of delivery. Factors associated with uptake and completion included symptom severity, available time and willingness to travel.ConclusionGiven effect sizes of couple-based interventions are similar to those reported in recent meta-analyses of patient-only and caregiver-only interventions (~d=.35-.45), it appears couple-based interventions for patients with cancer and their partners may be at least as efficacious as patient-only and caregiver-only interventions. Despite evidence that couple-based interventions enhance psycho-social adjustment for both patients and partners, these interventions have not yet been widely adopted. Although more work is needed to facilitate translation to routine practice, evidence reviewed is promising in reducing distress and improving coping and adjustment to a cancer diagnosis or to cancer symptoms.

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The immune composition of the tumor microenvironment regulates processes including angiogenesis, metastasis, and the response to drugs or immunotherapy. To facilitate the characterization of the immune component of tumors from transcriptomics data, a number of immune cell transcriptome signatures have been reported that are made up of lists of marker genes indicative of the presence a given immune cell population. The majority of these gene signatures have been defined through analysis of isolated blood cells. However, blood cells do not reflect the differentiation or activation state of similar cells within tissues, including tumors, and consequently markers derived from blood cells do not necessarily transfer well to tissues. To address this issue, we generated a set of immune gene signatures derived directly from tissue transcriptomics data using a network-based deconvolution approach. We define markers for seven immune cell types, collectively named ImSig, and demonstrate how these markers can be used for the quantitative estimation of the immune cell content of tumor and nontumor tissue samples. The utility of ImSig is demonstrated through the stratification of melanoma patients into subgroups of prognostic significance and the identification of immune cells with the use of single-cell RNA-sequencing data derived from tumors. Use of ImSig is facilitated by an R package (imsig). Cancer Immunol Res; 6(11); 1388-400. Ó2018 AACR.

The structural repertoire and kinetic threshold distinguishing legitimate signaling substrates are fundamental questions in proteolytic networks and pathways. We used N-terminal proteomics to address these issues by identifying cleavage-sites within the Escherichia coli proteome driven by the apoptotic signaling protease caspase-3 and the bacterial protease GluC. Defying the dogma that proteases cleave primarily in natively unstructured loops, we found that both caspase-3 and GluC cleave in α-helices nearly as frequently as extended loops. Strikingly, biochemical and kinetic characterization revealed that E. coli caspase-3 substrates were greatly inferior to natural substrates, suggesting protease/substrate co-evolution. Engineering an E. coli substrate to match natural catalytic rates defined a kinetic threshold depicting a signaling event. This unique combination of proteomics, biochemistry, kinetics and substrate engineering reveals new insights into the structure-function relationship of protease targets and their validation from large-scale approaches.

We have produced Csf1r-deficient rats by homologous recombination in embryonic stem cells. Consistent with the role of Csf1r in macrophage differentiation, there was a loss of peripheral blood monocytes, microglia in the brain, epidermal Langerhans cells, splenic marginal zone macrophages, bone-associated macrophages and osteoclasts, and peritoneal macrophages. Macrophages of splenic red pulp, liver, lung, and gut were less affected. The pleiotropic impacts of the loss of macrophages on development of multiple organ systems in rats were distinct from those reported in mice. Csf1r−/− rats survived well into adulthood with postnatal growth retardation, distinct skeletal and bone marrow abnormalities, infertility, and loss of visceral adipose tissue. Gene expression analysis in spleen revealed selective loss of transcripts associated with the marginal zone and, in brain regions, the loss of known and candidate novel microglia-associated transcripts. Despite the complete absence of microglia, there was little overt phenotype in brain, aside from reduced myelination and increased expression of dopamine receptor-associated transcripts in striatum. The results highlight the redundant and nonredundant functions of CSF1R signaling and of macrophages in development, organogenesis, and homeostasis.

Host dependency factors that are required for influenza A virus infection may serve as therapeutic targets as the virus is less likely to bypass them under drug-mediated selection pressure. Previous attempts to identify host factors have produced largely divergent results, with few overlapping hits across different studies. Here, we perform a genome-wide CRISPR/ Cas9 screen and devise a new approach, meta-analysis by information content (MAIC) to systematically combine our results with prior evidence for influenza host factors. MAIC outperforms other meta-analysis methods when using our CRISPR screen as validation data. We validate the host factors, WDR7, CCDC115 and TMEM199, demonstrating that these genes are essential for viral entry and regulation of V-type ATPase assembly. We also find that CMTR1, a human mRNA cap methyltransferase, is required for efficient viral cap snatching and regulation of a cell autonomous immune response, and provides synergistic protection with the influenza endonuclease inhibitor Xofluza.

BackgroundPeripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus of investigation.MethodsWe used microarray data on whole blood from two independent case-control studies of MDD: the GlaxoSmithKline–High-Throughput Disease-specific target Identification Program [GSK-HiTDiP] study (113 patients and 57 healthy control subjects) and the Janssen–Brain Resource Company study (94 patients and 100 control subjects). Genome-wide differential gene expression analysis (18,863 probes) resulted in a p value for each gene in each study. A Bayesian method identified the largest p-value threshold (q = .025) associated with twice the number of genes differentially expressed in both studies compared with the number of coincidental case-control differences expected by chance.ResultsA total of 165 genes were differentially expressed in both studies with concordant direction of fold change. The 90 genes overexpressed (or UP genes) in MDD were significantly enriched for immune response to infection, were concentrated in a module of the gene coexpression network associated with innate immunity, and included clusters of genes with correlated expression in monocytes, monocyte-derived dendritic cells, and neutrophils. In contrast, the 75 genes underexpressed (or DOWN genes) in MDD were associated with the adaptive immune response and included clusters of genes with correlated expression in T cells, natural killer cells, and erythroblasts. Consistently, the MDD patients with overexpression of UP genes also had underexpression of DOWN genes (correlation > .70 in both studies).ConclusionsMDD was replicably associated with proinflammatory activation of the peripheral innate immune system, coupled with relative inactivation of the adaptive immune system, indicating the potential of transcriptional biomarkers for immunological stratification of patients with depression.

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