Disruption of CD47-SIRPα signaling restores inflammatory function in tumor-associated myeloid-derived suppressor cells.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous immune population with diverse immunosuppressive functions in solid tumors. Here, we explored the role of the tumor microenvironment in regulating MDSC differentiation and immunosuppressive properties via signal-regulatory protein alpha (SIRPα)/CD47 signaling. In a murine melanoma model, we observed progressive increases in monocytic MDSCs and monocyte-derived dendritic cells that exhibited potent T cell-suppressive capabilities. These adaptations could be recapitulated in vitro by exposing hematopoietic stem cells to tumor-derived factors. Engagement of CD47 with SIRPα on myeloid cells reduced their phagocytic capability, enhanced expression of immune checkpoints, increased reactive oxygen species production, and suppressed T cell proliferation. Perturbation of SIRPα signaling restored phagocytosis and antigen presentation by MDSCs, which was accompanied by renewed T cell activity and delayed tumor growth in multiple solid cancers. These data highlight that therapeutically targeting myeloid functions in combination with immune checkpoint inhibitors could enhance anti-tumor immunity.

Connecting omics signatures and revealing biological mechanisms with iLINCS.

There are only a few platforms that integrate multiple omics data types, bioinformatics tools, and interfaces for integrative analyses and visualization that do not require programming skills. Here we present iLINCS ( http://ilincs.org ), an integrative web-based platform for analysis of omics data and signatures of cellular perturbations. The platform facilitates mining and re-analysis of the large collection of omics datasets (>34,000), pre-computed signatures (>200,000), and their connections, as well as the analysis of user-submitted omics signatures of diseases and cellular perturbations. iLINCS analysis workflows integrate vast omics data resources and a range of analytics and interactive visualization tools into a comprehensive platform for analysis of omics signatures. iLINCS user-friendly interfaces enable execution of sophisticated analyses of omics signatures, mechanism of action analysis, and signature-driven drug repositioning. We illustrate the utility of iLINCS with three use cases involving analysis of cancer proteogenomic signatures, COVID 19 transcriptomic signatures and mTOR signaling.

An Observational Study of Paediatric Preoperative Transfusion Practice in a Resource-Limited Setting.

BACKGROUND: Paediatric anaemia is highly prevalent in low-middle-income countries and can negatively impact postoperative outcomes. Currently, there are no guidelines for the management of paediatric preoperative anaemia. To ensure optimal care in resource-limited settings: balancing the risks of anaemia and using resources such as blood transfusion, we first need to understand current practices. To address this, a joint UK-Bangladesh team conducted an observational study at a paediatric surgical centre in Bangladesh. METHODS: A total of 464 patients ≤16 years who underwent elective and emergency surgery were categorised into major (351/464), moderate (92/464) and minor (21/464) surgery groups according to anticipated blood loss. Preoperative anaemia testing and transfusion was assessed retrospectively through patient notes. RESULTS: Median age was 4 years and 73% were male. 32.5% (151/464) patients had preoperative blood testing for anaemia. 17.5% (81/464) children were transfused preoperatively. Of those children transfused, 40.7% (33/81) underwent transfusion solely based on visible signs of anaemia on clinical examination. Seventy-five percentage (36/48) of children who underwent transfusion after blood testing had haemoglobin ≥80 g/L. Major surgery category had the highest proportion of children who were transfused and tested for anaemia. CONCLUSION: A liberal transfusion approach is evident here. Discussion with local clinicians revealed that this was due to limitations in obtaining timely blood results and reduction in laboratory costs incurred by families when clinical suspicion of anaemia was high. Further research is needed to analyse the potential of using bedside haemoglobin testers in conjunction with patient blood management strategies to limit blood transfusions and its associated risks.

ALOHA: Aggregated local extrema splines for high-throughput dose-response analysis.

Computational methods for genomic dose-response integrate dose-response modeling with bioinformatics tools to evaluate changes in molecular and cellular functions related to pathogenic processes. These methods use parametric models to describe each gene's dose-response, but such models may not adequately capture expression changes. Additionally, current approaches do not consider gene co-expression networks. When assessing co-expression networks, one typically does not consider the dose-response relationship, resulting in 'co-regulated' gene sets containing genes having different dose-response patterns. To avoid these limitations, we develop an analysis pipeline called Aggregated Local Extrema Splines for High-throughput Analysis (ALOHA), which computes individual genomic dose-response functions using a flexible class Bayesian shape constrained splines and clusters gene co-regulation based upon these fits. Using splines, we reduce information loss due to parametric lack-of-fit issues, and because we cluster on dose-response relationships, we better identify co-regulation clusters for genes that have co-expressed dose-response patterns from chemical exposure. The clustered pathways can then be used to estimate a dose associated with a pre-specified biological response, i.e., the benchmark dose (BMD), and approximate a point of departure dose corresponding to minimal adverse response in the whole tissue/organism. We compare our approach to current parametric methods and our biologically enriched gene sets to cluster on normalized expression data. Using this methodology, we can more effectively extract the underlying structure leading to more cohesive estimates of gene set potency.

Surgical decision making around paediatric preoperative anaemia in low-income and middle-income countries.

Prevalence of anaemia is high among children in low-income and middle-income countries. Anaemia is an important factor to consider preoperatively as low haemoglobin concentrations can have a negative effect on surgical outcomes and can also lead to surgeries being cancelled or postponed, which can have adverse health implications and stretch already limited resources in these countries. Additionally, blood transfusions to correct anaemia exposes children to safety issues. Therefore, where anaemia is known to be prevalent and resources are scarce, a contextually appropriate and relatively safe minimum haemoglobin concentration for proceeding to surgery could substantially improve patient management and efficiency of the health system. In this Review, we consider why paediatric anaemia is a major public health issue in low-income and middle-income countries, the value of preoperative testing of anaemia, and methods of optimising haemoglobin concentrations in the context of paediatric surgeries taking place in resource-limited settings.

Acceptability of the Hall Technique to parents and children.

OBJECTIVE: To investigate the acceptability of stainless steel crowns placed by dental therapists on children's primary molars using the Hall Technique. DESIGN: Mixed methods approach, using qualitative inductive analysis and quantitative analysis. SETTING: Hawke's Bay Community Oral Health Service METHODS: One focus group was conducted and ten thirty-minute phone interviews were undertaken with parents of children who had previously had a stainless steel crown placed using the Hall Technique (over the period 1 December 2011 to 31 May 2012). An inductive approach was used to analyse the qualitative research data, and the information was arranged into several categories based on the key themes which arose. Children treated with the Hall Technique were asked immediately after treatment whether they had enjoyed their visit to the clinic that day. RESULTS: Common themes were found with regard to appearance, pain, the procedure, and general opinions on acceptability. Nearly all (90%) of the children responded positively about their visit to the clinic. CONCLUSION: There was a high degree of acceptance among both parents and children for stainless steel crown placement using the Hall Technique in this group.