Tumor-specific draining lymph node CD8 T cells orchestrate an anti-tumor response to neoadjuvant PD-1 immune checkpoint blockade.

Elucidating the anti-tumor role of tumor-draining lymph nodes (tdLNs) in patients could offer critical mechanistic insight and shift therapeutic strategies from a tumor-centric approach to one that considers tumor-immune system interplay. Our study characterizes benign tdLNs T cell anti-tumor responses beyond initial T cell priming in patients with resectable non-small cell lung cancer. We further investigated whether tumor-specific tdLN T cells were altered by immune checkpoint blockade (ICB) locally and systemically.

Team resuscitation for paediatrics (TRAP); application and validation of a paediatric resuscitation quality instrument in non-simulated resuscitations.

Background: Resuscitation of paediatric cardiac and respiratory arrest is a high-stakes and low frequency event in the paediatric emergency department. Resuscitation team performance assessment tools have been developed and validated for use in the simulation environment, but no tool currently exists to evaluate clinical performance in non-simulated, live paediatric resuscitations.

Methods: This is a validation study assessing inter-rater reliability of a novel assessment tool of clinical performance of non-simulated resuscitations, the Team Resuscitation for Paediatrics tool.

Acquisition of discrete immune suppressive barriers contributes to the initiation and progression of preinvasive to invasive human lung cancer.

Computerized chest tomography (CT)-guided screening in populations at risk for lung cancer has increased the detection of preinvasive subsolid nodules, which progress to solid invasive adenocarcinoma. Despite the clinical significance, there is a lack of effective therapies for intercepting the progression of preinvasive to invasive adenocarcinoma. To uncover determinants of early disease emergence and progression, we used integrated single-cell approaches, including scRNA-seq, multiplexed imaging mass cytometry and spatial transcriptomics, to construct the first high-resolution map of the composition, lineage/functional states, developmental trajectories and multicellular crosstalk networks from microdissected non-solid (preinvasive) and solid compartments (invasive) of individual part-solid nodules.

Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1 progenitor CD8 T cells to improve immunotherapy.

TCF1 progenitor CD8 T cells mediate the efficacy of immunotherapy; however, the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1 progenitor-exhausted-like phenotype and increased responsiveness to PD-1 blockade in vivo. PKM2 CD8 T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites and increased PPP cycling as determined by 1,2-C glucose carbon tracing.

Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve checkpoint blockade.

TCF1 progenitor CD8+ T cells mediate the efficacy of PD-1 blockade, however the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1 central memory-like phenotype and increased responsiveness to PD-1 blockade . PKM2 CD8+ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites, and increased PPP cycling as determined by 1,2 C glucose carbon tracing.

Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer.

IRE1α-XBP1 signaling is emerging as a central orchestrator of malignant progression and immunosuppression in various cancer types. Employing a computational XBP1s detection method applied to TCGA datasets, we demonstrate that expression of the XBP1s mRNA isoform predicts poor survival in non-small cell lung cancer (NSCLC) patients. Ablation of IRE1α in malignant cells delays tumor progression and extends survival in mouse models of NSCLC.

Expression of the mono-ADP-ribosyltransferase ART1 by tumor cells mediates immune resistance in non-small cell lung cancer.

Most patients with non-small cell lung cancer (NSCLC) do not achieve durable clinical responses from immune checkpoint inhibitors, suggesting the existence of additional resistance mechanisms. Nicotinamide adenine dinucleotide (NAD)-induced cell death (NICD) of P2X7 receptor (P2X7R)-expressing T cells regulates immune homeostasis in inflamed tissues. This process is mediated by mono-adenosine 5'-diphosphate (ADP)-ribosyltransferases (ARTs).

Medication Errors in Pediatric Patients after Implementation of a Field Guide with Volume-Based Dosing.

Background: Several studies have demonstrated the high frequency of medication errors in pediatric patients by prehospital providers during both patient care and simulation. In 2015, our hospital-based urban EMS system introduced the Handtevy Field Guide that provides precalculated pediatric doses in milliliters (mL) by patient age. We hypothesized that implementation of the Field Guide would increase the percentage of correct pediatric medication doses to greater than 85%.

Intratumoral stem-like CCR4+ regulatory T cells orchestrate the immunosuppressive microenvironment in HCC associated with hepatitis B.

Background & Aims: Regulatory T cell (Treg) depletion increases antitumor immunity. However, severe autoimmunity can occur following systemic loss of Tregs, which could be avoided by selectively depleting intratumoral Tregs. Herein, we aimed to investigate the role of tumor-infiltrating CCR4 Tregs in hepatocellular carcinoma (HCC) and to provide a potential target strategy for immunotherapy.

Tim-4 cavity-resident macrophages impair anti-tumor CD8 T cell immunity.

Immune checkpoint blockade (ICB) has been a remarkable clinical advance for cancer; however, the majority of patients do not respond to ICB therapy. We show that metastatic disease in the pleural and peritoneal cavities is associated with poor clinical outcomes after ICB therapy. Cavity-resident macrophages express high levels of Tim-4, a receptor for phosphatidylserine (PS), and this is associated with reduced numbers of CD8 T cells with tumor-reactive features in pleural effusions and peritoneal ascites from patients with cancer.

Hepatitis B-Induced IL8 Promotes Hepatocellular Carcinoma Venous Metastasis and Intrahepatic Treg Accumulation.

Hepatitis B-associated hepatocellular carcinoma (HCC) is often accompanied by severe vascular invasion and portal vein tumor thrombus, leading to a poor prognosis. However, the underlying mechanism of this disease remains obscure. In this study, we demonstrate that the hepatitis B virus (HBV)-encoded gene HBx induces high IL8 production through MEK-ERK signal activation, leading to enhanced endothelial permeability to facilitate tumor vascular invasion.

Impact of prehospital pediatric asthma management protocol adherence on clinical outcomes.

Objective: To evaluate the frequency of EMS protocol non-adherence during pediatric asthma encounters and its association with emergency department (ED) length of stay (LOS) and hospital admission.

Methods: This is a retrospective review of asthma encounters aged 2-17 years transported by EMS to a pediatric ED from 2012 to 2017. Our primary outcome was hospital admission based on prehospital protocol adherence defined as: (1) bronchodilator administration, (2) treatment of hypoxia with oxygen, or (3) administration of intramuscular (IM) epinephrine in encounters with high severity of distress.

CCL22 signaling contributes to sorafenib resistance in hepatitis B virus-associated hepatocellular carcinoma.

The HBV-initiated hepatocellular carcinoma (HCC) frequently develops from or accompanies long-term chronic hepatitis, inflammation, and cirrhosis, and has a poor prognosis. Sorafenib, an orally active multi-kinase inhibitor, currently the most common approved drug for first-line systemic treatment of advanced HCC, only improves overall survival of three months, suggesting the need for new therapeutic strategies. In this study, we identified that sorafenib selectively resisted in immune competent C57BL/6 mice but not nude mice.

The lung microenvironment: an important regulator of tumour growth and metastasis.

Lung cancer is a major global health problem, as it is the leading cause of cancer-related deaths worldwide. Major advances in the identification of key mutational alterations have led to the development of molecularly targeted therapies, whose efficacy has been limited by emergence of resistance mechanisms. US Food and Drug Administration (FDA)-approved therapies targeting angiogenesis and more recently immune checkpoints have reinvigorated enthusiasm in elucidating the prognostic and pathophysiological roles of the tumour microenvironment in lung cancer.

Distinct Receptor Tyrosine Kinase Subsets Mediate Anti-HER2 Drug Resistance in Breast Cancer.

Targeted inhibitors of the human epidermal growth factor receptor 2 (HER2), such as trastuzumab and lapatinib, are among the first examples of molecularly targeted cancer therapy and have proven largely effective for the treatment of HER2-positive breast cancers. However, approximately half of those patients either do not respond to these therapies or develop secondary resistance. Although a few signaling pathways have been implicated, a comprehensive understanding of mechanisms underlying HER2 inhibitor drug resistance is still lacking.

Noncoding RNAs Regulating Cancer Signaling Network.

The cellular signaling network plays a fundamental role during development and disease, especially cancer progression. By deregulating signaling pathways, cancer cells acquire hallmarks of the disease including uncontrolled proliferation, evasion from cell death, activation of angiogenesis, invasion, and metastasis. Noncoding RNAs make substantial contributions to regulating signal transduction in cancer, thereby promoting or suppressing different biological processes during tumorigenesis.

Isolation of Glioma-Initiating Cells for Biological Study.

Glioblastoma multiforme (GBM, WHO grade IV astrocytoma) is the most common and lethal primary brain tumor in adults, with an average survival of slightly more than 1 year after initial diagnosis. GBMs display significant heterogeneity within the tumor mass, among which a subpopulation of cells called glioma-initiating cells (GICs) is responsible for tumorigenesis and resistance to conventional therapies. Therefore, understanding the mechanism underlying the biological properties of GICs would help develop better therapies to target this population for GBM treatment.

MiR-148a functions to suppress metastasis and serves as a prognostic indicator in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) presents a major challenge in the clinic due to its lack of reliable prognostic markers and targeted therapies. Accumulating evidence strongly supports the notion that microRNAs (miRNAs) are involved in tumorigenesis and could serve as biomarkers for diagnostic purposes. To identify miRNAs that functionally suppress metastasis of TNBC, we employed a concerted approach with selecting miRNAs that display differential expression profiles from bioinformatic analyses of breast cancer patient databases and validating top candidates with functional assays using breast cancer cell lines and mouse models.

Inflammation-Dependent IL18 Signaling Restricts Hepatocellular Carcinoma Growth by Enhancing the Accumulation and Activity of Tumor-Infiltrating Lymphocytes.

Chronic inflammation in liver tissue is an underlying cause of hepatocellular carcinoma. High levels of inflammatory cytokine IL18 in the circulation of patients with hepatocellular carcinoma correlates with poor prognosis. However, conflicting results have been reported for IL18 in hepatocellular carcinoma development and progression.

TGF-β-Regulated MicroRNAs and Their Function in Cancer Biology.

The transforming growth factor-β (TGF-β) is known to regulate a large number of biological processes and is involved in various aspects of tumor development. Recent studies have shown that the biogenesis of miRNAs can be regulated by TGF-β signaling directly via Smad-dependent mechanisms and/or other unknown mechanisms, which may induce autoregulatory feedback loops in response to the activation of TGF-β signaling, influencing the fate of tumor cells. In this chapter, we summarize the currently described mechanisms underlying TGF-β's regulation of miRNA biogenesis, and the functional role of TGF-β-regulated miRNAs in tumor initiation, epithelial-mesenchymal transition, and tumor microenvironment modulation.

Inflammatory models drastically alter tumor growth and the immune microenvironment in hepatocellular carcinoma.

Initiation and progression of hepatocellular carcinoma (HCC) is intimately associated with a chronically diseased liver tissue. This diseased liver tissue background is a drastically different microenvironment from the healthy liver, especially with regard to immune cell prevalence and presence of mediators of immune function. To better understand the consequences of liver disease on tumor growth and the interplay with its microenvironment, we utilized two standard methods of fibrosis induction and orthotopic implantation of tumors into the inflamed and fibrotic liver to mimic the liver condition in human HCC patients.