The health benefits of passive heating and aerobic exercise: to what extent do the mechanisms overlap?

Exercise can induce numerous health benefits that can reduce the risk of chronic diseases and all-cause mortality, yet a significant percentage of the population do not meet minimal physical activity guidelines. Several recent studies have shown that passive heating can induce numerous health benefits, many of which are comparable to exercise, such as improvements to cardiorespiratory fitness, vascular health, glycaemic control and chronic low-grade inflammation. As such, passive heating is emerging as a promising therapy for populations who cannot perform sustained exercise or display poor exercise adherence. There appears to be some overlap between the cellular signalling responses that are regulated by temperature and the mechanisms that underpin beneficial adaptations to exercise, but detailed comparisons have not yet been made. Therefore, the purpose of this mini review is to assess the similarities and distinctions between adaptations to passive heating and exercise. Understanding the potential shared mechanisms of action between passive heating and exercise may help to direct future studies to implement passive heating more effectively and identify differences between passive heating and exercise induced adaptations

Maternal Style Selectively Shapes Amygdalar Development and Social Behavior in Rats Genetically Prone to High Anxiety

The early-life environment critically influences neurodevelopment and later psychological health. To elucidate neural and environmental elements that shape emotional behavior, we developed a rat model of individual differences in temperament and environmental reactivity. We selectively bred rats for high vs. low behavioral response to novelty and found that high reactive (bHR) rats display greater risk-taking, impulsivity, and aggression relative to low reactive (bLR) rats, which show high levels of anxiety/depression-like behavior and certain stress vulnerability. The bHR/bLR traits are heritable but prior work revealed bHR/bLR maternal style differences, with bLR dams showing more maternal attention than bHRs. The present study implemented a cross-fostering paradigm to examine the contribution of maternal behavior on bLR offspring’s brain development and emotional behavior. bLR offspring were reared by biological bLR mothers or fostered to a bLR or bHR mother and then evaluated to determine effects on: 1) developmental gene expression in the hippocampus and amygdala; and 2) adult anxiety/depression-like behavior. Genome-wide expression profiling showed that cross-fostering bLR rats to bHR mothers shifted developmental gene expression in the amygdala (but not hippocampus), reduced adult anxiety and enhanced social interaction. Our findings illustrate how an early-life manipulation such as cross-fostering changes the brain’s developmental trajectory and ultimately impacts adult behavior. Moreover, while earlier studies highlighted hippocampal differences contributing to the bHR/bLR phenotypes, our results point to a role of the amygdala as well. Future work will pursue genetic and cellular mechanisms within the amygdala that contribute to bHR/bLR behavior either at baseline or following environmental manipulations

G-CSF induces CD15(+) CD14(+) cells from granulocytes early in the physiological environment of pregnancy and the cancer immunosuppressive microenvironment

OBJECTIVES: Recombinant granulocyte colony‐stimulating factor (G‐CSF) is frequently administered to patients with cancer to enhance granulocyte recovery post‐chemotherapy. Clinical trials have also used G‐CSF to modulate myeloid cell function in pregnancy and inflammatory diseases. Although the contribution of G‐CSF to expanding normal granulocytes is well known, the effect of this cytokine on the phenotype and function of immunosuppressive granulocytic cells remains unclear. Here, we investigate the impact of physiological and iatrogenic G‐CSF on an as yet undescribed granulocyte phenotype and ensuing outcome on T cells in the settings of cancer and pregnancy. METHODS: Granulocytes from patients treated with recombinant G‐CSF, patients with late‐stage cancer and women enrolled on a trial of recombinant G‐CSF were phenotyped by flow cytometry. The ability and mechanism of polarised granulocytes to suppress T‐cell proliferation were assessed by cell proliferation assays, flow cytometry and ELISA. RESULTS: We observed that G‐CSF leads to a significant upregulation of CD14 expression on CD15(+) granulocytes. These CD15(+)CD14(+) cells are identified in the blood of patients with patients undergoing neutrophil mobilisation with recombinant G‐CSF, and physiologically in women early in pregnancy or in those treated as a part of a clinical trial. Immunohistochemistry of tumor tissue or placental tissue identified the expression of G‐CSF. The G‐CSF upregulates the release of reactive oxygen species (ROS) in CD15(+)CD14(+) cells leading to the suppression of T‐cell proliferation. CONCLUSIONS: G‐CSF induces a population of ROS(+) immunosuppressive CD15(+)CD14(+) granulocytes. Strategies for how recombinant G‐CSF can be scheduled to reduce effects on T‐cell therapies should be developed in future clinical studies

Risk factors for late bowel and bladder toxicities in NRG Oncology prostate cancer trials of high-risk patients: A meta-analysis of physician-rated toxicities

Purpose: A meta-analysis of sociodemographic variables and their association with late (\u3e180 days from start of radiation therapy[RT]) bowel, bladder, and clustered bowel and bladder toxicities was conducted in patients with high-risk (clinical stages T2c-T4b or Gleason score 8-10 or prostate-specific antigen level \u3e20) prostate cancer. Methods and materials: Three NRG trials (RTOG 9202, RTOG 9413, and RTOG 9406) that accrued from 1992 to 2000 were used. Late toxicities were measured with the Radiation Therapy Oncology Group Late Radiation Morbidity Scale. After controlling for study, age, Karnofsky Performance Status, and year of accrual, sociodemographic variables were added to the model for each outcome variable of interest in a stepwise fashion using the Fine-Gray regression models with an entry criterion of 0.05. Results: A total of 2432 patients were analyzed of whom most were Caucasian (76%), had a KPS score of 90 to 100 (92%), and received whole-pelvic RT+HT (67%). Of these patients, 13 % and 16% experienced late grade ≥2 bowel and bladder toxicities, respectively, and 2% and 3% experienced late grade ≥3 bowel and bladder toxicities, respectively. Late grade ≥2 clustered bowel and bladder toxicities were seen in approximately 1% of patients and late grade ≥3 clustered toxicities were seen in 2 patients ( Conclusions: Patients with high-risk prostate cancer who receive whole-pelvic RT+LT HT are more likely to have a grade ≥2 bowel toxicity than those who receive prostate-only RT. LT bowel and bladder toxicities were infrequent. Future studies will need to confirm these findings utilizing current radiation technology and patient-reported outcomes

Inhibitor-Sensitive FGFR2 and FGFR3 Mutations in Lung Squamous Cell Carcinoma

A comprehensive description of genomic alterations in lung squamous cell carcinoma (lung SqCC) has recently been reported, enabling the identification of genomic events that contribute to the oncogenesis of this disease. In lung SqCC, one of the most frequently altered receptor tyrosine kinase families is the fibroblast growth factor receptor (FGFR) family, with amplification or mutation observed in all four family members. Here, we describe the oncogenic nature of mutations observed in FGFR2 and FGFR3, which are each observed in 3% of samples, for a mutation rate of 6% across both genes. Using cell culture and xenograft models, we show that several of these mutations drive cellular transformation. Transformation can be reversed by small molecule FGFR inhibitors currently being developed for clinical use. We also show that mutations in the extracellular domains of FGFR2 lead to constitutive FGFR dimerization. Additionally, we report a patient with an FGFR2-mutated oral squamous cell carcinoma who responded to the multi-targeted tyrosine kinase inhibitor pazopanib. These findings provide new insights into driving oncogenic events in a subset of lung squamous cancers, and recommend future clinical studies with FGFR inhibitors in patients with lung and head and neck SqCC

Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors

The success in lung cancer therapy with Programmed Death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between Epidermal Growth Factor Receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, cytotoxic T lymphocyte antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased cytotoxic T cells and increased markers of T cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape, and mechanistically link treatment response to PD-1 inhibition

The genetic landscape of high-risk neuroblastoma

Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%1. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 cases using a combination of whole exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median exonic mutation frequency of 0.60 per megabase (0.48 non-silent), and remarkably few recurrently mutated genes in these tumors. Genes with significant somatic mutation frequencies included ALK (9.2% of cases), PTPN11 (2.9%), ATRX (2.5%, an additional 7.1% had focal deletions), MYCN (1.7%, a recurrent p.Pro44Leu alteration), and NRAS (0.83%). Rare, potentially pathogenic germline variants were significantly enriched in ALK, CHEK2, PINK1, and BARD1. The relative paucity of recurrent somatic mutations in neuroblastoma challenges current therapeutic strategies reliant upon frequently altered oncogenic drivers