Hot water immersion induces an acute cytokine response in cervical spinal cord injury

Purpose: The dysfunctional sympathetic nervous system in individuals with cervical spinal cord injury (CSCI) impairs adrenergic responses and may, therefore, contribute to the blunted post-exercise cytokine response. The purpose of this study was to investigate an alternative way to exercise to induce an acute cytokine response by passive core temperature elevation in CSCI. Methods: Seven male participants with a motor complete CSCI and 8 male able-bodied controls were immersed for 60 min in water set at a temperature 2 °C above the individuals’ resting oesophageal temperature. Blood was collected pre, post, and every hour up to 4 h post-immersion. Results: Hot water immersion resulted in an IL-6 plasma concentration mean increase of 133 ± 144 % in both groups (P = 0.001). On a group level, IL-6 plasma concentrations were 68 ± 38 % higher in CSCI (P = 0.06). In both groups, IL-8 increased by 14 ± 11 % (P = 0.02) and IL-1ra by 18 ± 17 % (P = 0.05). Catecholamine plasma concentrations were significantly reduced in CSCI (P < 0.05) and did not increase following immersion. Conclusions: Passive elevation of core temperature acutely elevates IL-6, IL-8 and IL-1ra in CSCI despite a blunted adrenergic response, which is in contrast to earlier exercise interventions in CSCI. The present study lays the foundation for future studies to explore water immersion as an alternative to exercise to induce an acute cytokine response in CSCI

Outcome and human epidermal growth factor receptor (HER) 1–4 status in invasive breast carcinomas with proliferation indices evaluated by bromodeoxyuridine labelling

BACKGROUND: We have shown previously that whereas overexpression of human epidermal growth factor receptor (HER)1, HER2 and HER3 is associated with poor prognosis in breast cancer, HER4 is associated with a good prognosis. Cell proliferation is a key component of aggressive cancers and is driven by growth factors. In this study, bromodeoxyuridine (BrdU)-derived proliferation indices are correlated with clinical outcome and HER1–4 status for further clarification of the differing roles for the HER family at a biological level. METHODS: Seventy-eight invasive breast cancers had BrdU labelling in vivo to determine the BrdU labelling index (BLI) and the potential tumour doubling time (T(pot)). Long-term clinical follow-up was available for these patients. We used immunohistochemistry to establish the HER1–4 status in 55 patients from the BrdU cohort. RESULTS: We demonstrate a significant correlation between high BLI values and breast cancer-specific death (P = 0.0174). Low T(pot )times were also significantly correlated with breast cancer-specific death (P = 0.0258). However, BLI did not independently predict survival in Cox's multiple regression analysis when combined with other prognostic factors such as size, grade and nodal status. Tumours found to be positive for HER1, HER2 or HER3 had significantly (P = 0.041) higher labelling indices, with HER1 also showing significantly higher indices when considered independently (P = 0.024). Conversely, HER4 positivity was significantly correlated (P = 0.013) with low BLI values, in line with previous data associating this receptor with good prognosis tumours. CONCLUSIONS: These results support the hypothesis that HER1–3 are associated with driving tumour proliferation, whereas HER4 is involved in a non-proliferative or even protective role

HER2 therapy. HER2 (ERBB2): functional diversity from structurally conserved building blocks

EGFR-type receptor tyrosine kinases achieve a broad spectrum of cellular responses by utilizing a set of structurally conserved building blocks. Based on available crystal structures and biochemical information, significant new insights have emerged into modes of receptor control, its deregulation in cancer, and the nuances that differentiate the four human receptors. This review gives an overview of current models of the control of receptor activity with a special emphasis on HER2 and HER3

Consequences of replacing EGFR juxtamembrane domain with an unstructured sequence.

PMC3497011EGFR is the best studied receptor tyrosine kinase. Yet, a comprehensive mechanistic understanding of EGFR signaling is lacking, despite very active research in the field. In this paper, we investigate the role of the juxtamembrane (JM) domain in EGFR signaling by replacing it with a (GGS)(10) unstructured sequence. We probe the effect of this replacement on (i) EGFR phosphorylation, (ii) EGFR dimerization and (iii) ligand (EGF) binding. We show that the replacement of EGFR JM domain with a (GGS)(10) unstructured linker completely abolishes the phosphorylation of all tyrosine residues, without measurable effects on receptor dimerization or ligand binding. Our results suggest that the JM domain does not stabilize the inactive EGFR dimer in the absence of ligand, and is likely critical only for the last step of EGFR activation, the ligand-induced transition from the inactive to active dimer.JH Libraries Open Access Fun