BackgroundDespite the high prevalence of epidermal growth factor receptor (EGFR) overexpression in head and neck squamous cell carcinomas (HNSCCs), incorporation of the EGFR inhibitor cetuximab into the clinical management of HNSCC has not led to significant changes in long-term survival outcomes. Therefore, the identification of novel therapeutic approaches to enhance the clinical efficacy of cetuximab could lead to improved long-term survival for HNSCC patients. Our previous work suggests that EGFR inhibition activates the interleukin-1 (IL-1) pathway via tumor release of IL-1 alpha (IL-1α), although the clinical implications of activating this pathway are unclear in the context of cetuximab therapy. Given the role of IL-1 signaling in anti-tumor immune response, we hypothesized that increases in IL-1α levels would enhance tumor response to cetuximab.MethodsParental and stable myeloid differentiation primary response gene 88 (MyD88) and IL-1 receptor 1 (IL-1R1) knockdown HNSCC cell lines, an IL-1R antagonist (IL-1RA), neutralizing antibodies to IL-1α and IL-1β, and recombinant IL-1α and IL-1β were used to determine cytokine production (using ELISA) in response to cetuximab in vitro. IL-1 pathway modulation in mouse models was accomplished by administration of IL-1RA, stable overexpression of IL-1α in SQ20B cells, administration of rIL-1α, and administration of a polyanhydride nanoparticle formulation of IL-1α. CD4+ and CD8+ T cell-depleting antibodies were used to understand the contribution of T cell-dependent anti-tumor immune responses. Baseline serum levels of IL-1α were measured using ELISA from HNSCC patients treated with cetuximab-based therapy and analyzed for association with progression free survival (PFS).ResultsCetuximab induced pro-inflammatory cytokine secretion from HNSCC cells in vitro which was mediated by an IL-1α/IL-1R1/MyD88-dependent signaling pathway. IL-1 signaling blockade did not affect the anti-tumor efficacy of cetuximab, while increased IL-1α expression using polyanhydride nanoparticles in combination with cetuximab safely and effectively induced a T cell-dependent anti-tumor immune response. Detectable baseline serum levels of IL-1α were associated with a favorable PFS in cetuximab-based therapy-treated HNSCC patients compared to HNSCC patients with undetectable levels.ConclusionsAltogether, these results suggest that IL-1α in combination with cetuximab can induce a T cell-dependent anti-tumor immune response and may represent a novel immunotherapeutic strategy for EGFR-positive HNSCCs.Electronic supplementary materialThe online version of this article (10.1186/s40425-019-0550-z) contains supplementary material, which is available to authorized users.
Multiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system (CNS). Its corresponding animal model, experimental autoimmune encephalomyelitis (EAE), is widely used to understand disease pathogenesis and test novel therapeutic agents. However, existing methods to score EAE disease severity are subjective and often vary between individual researchers, making it difficult to translate findings across different studies. An enhanced automated method of disease scoring would eliminate subjectivity and reduce operator-dependent errors. Here, we used an Infra-Red Activity Monitoring System (IRAMS) to measure murine locomotor activity as a surrogate measure of disease severity and compared it to standard EAE scoring methods. In mice immunized with CNS-specific myelin antigens, we observed an inverse correlation between disease severity and mouse activity, with the IRAMS showing enhanced disease scoring compared to standard EAE scoring methods. Relative to standard EAE scoring methods, IRAMS showed comparable measurement of disease relapses and remissions in the SJL/J-relapsing-remitting model of EAE, and could comparably assess the therapeutic efficiency of the MS drug, Copaxone (Glatiramer acetate-GA). Thus, the IRAMS is a method to measure disease severity in EAE without subjective bias and is a tool to consistently assess the efficacy of novel therapeutic agents for MS.
OBJECTIVES: To evaluate the feasibility of using a biobehavioral approach to examine symptom burden in rural residents with advanced cancer. SAMPLE & SETTING: 21 patients with advanced lung, colorectal, or pancreatic cancer were enrolled at the University of Iowa in Iowa City. METHODS & VARIABLES: Using Cleeland’s cytokine-immunologic model of symptom expression, symptom burden (i.e., severity, count, and interference) and inflammatory cytokines were measured for 24 weeks. Potential predictors included demographics, clinical characteristics, optimism, social support, and cancer-related stress. Descriptive statistics, Wilcoxon rank-sum, and Fisher’s exact test were used for analysis. RESULTS: Recruitment and retention rates were similar for rural and nonrural patients. Demographics, optimism, and social support were no different between groups. The cancer-related stress total score for rural patients was nearly half of the score of nonrural patients, with rural patients reporting significantly less avoidance. Symptom severity for the five worst symptoms remained moderate during the 24 weeks, whereas nonrural residents reported steady declines in severity of their five worst symptoms. Significant differences in inflammatory cytokines between groups were only found at one time point. IMPLICATIONS FOR NURSING: Rural residents who seek care at a cancer center may be clinically and demographically more similar to their nonrural counterparts than to rural residents seeking local care.
Objectives: Negative bias against people who use illicit drugs adversely affects the care that they receive throughout the hospital. We hypothesized that emergency providers would display stronger negative bias toward these patients due to life-threatening contexts in which they treat this population. We also hypothesized that negative implicit bias would be associated with negative explicit bias. Methods: Faculty, nurses, and trainees at a midwestern tertiary care academic hospital were invited (June 26, 2019-September 5, 2019) to complete an online implicit association test and explicit bias survey. Results: Mean implicit association test results did not vary across demographics (n = 79). There were significant differences in explicit bias scores between departments regarding whether patients who use drugs deserve quality healthcare access ( P = 0.017). We saw no significant associations between implicit and explicit bias scores. Conclusion: Though limited by sample size, the results indicate that emergency and obstetrics/gynecology providers display more negative explicit bias toward this patient population than other providers.
Inhibition of interleukin-6 trans-signaling by sgp130Fc is anti-tumorigenic in head and neck squamous cell carcinoma. Background: Head and neck squamous cell carcinoma (HNSCC) is a highly inflammatory cancer type, and interleukin-6 (IL-6) is associated with this phenotype. Elevated expression of IL-6 is linked to tumor progression, recurrence, metastasis, and resistance to therapy in HNSCC. However, targeting IL-6 or IL-6 receptor (IL-6R) has demonstrated little to no clinical efficacy. IL-6 signals through a classical signaling pathway via membrane IL-6R or a trans-signaling pathway via soluble IL-6R (sIL-6R). Recent evidence suggests that classical signaling induces acute, transient inflammation, eventually resulting in homeostasis; whereas trans-signaling may induce chronic, pro-tumorigenic inflammation. Therefore we propose that IL-6 trans-signaling is associated with the pro-inflammatory phenotype observed in HNSCC. We wanted to determine whether inhibition of IL-6 trans-signaling by sgp130Fc would better demonstrate anti-tumor efficacy and increase HNSCC tumor response to radiation, chemotherapy, and targeted therapy (cetuximab) compared to global IL-6 pathway inhibition. Method/Results: Baseline levels of IL-6, IL-6R, sIL-6R, and sgp130 proteins in HNSCC cells were determined using ELISA and flow cytometry. Cisplatin, radiation, and cetuximab treatments each induced HNSCC cell secretion of IL-6 and sIL-6R in vitro, yet adding sgp130Fc to those treatments did not further reduce clonogenic survival. Sgp130Fc treatment significantly suppressed SQ20B tumor growth in nude mice, whereas global IL-6 pathway inhibition by IL-6R antagonist tocilizumab did not; however, cetuximab reduced the efficacy of sgp130Fc in this animal model. Sgp130Fc also sensitized SQ20B xenograft tumors to radiation and chemotherapy in nude mice and suppressed SCCVII tumor growth in male but not female C3H/HeJ mice. Conclusion: Inhibition of IL-6 trans-signaling by sgp130Fc displayed significant antitumor effects as a single therapy and sensitized resistant HNSCC tumors to radiation and chemotherapy in vivo; however, sgp130Fc did not reduce survival of HNSCC cells in vitro. These results suggest that the efficacy of sgp130Fc relies on targeting another part of the microenvironment instead of tumor cells directly. Sgp130Fc has promise both as a single therapy and potentially as combined therapy with radiation and chemotherapy in HNSCC. Chapter 1: Introduction Section I: Head and neck squamous cell carcinoma (HNSCC) Etiology and statistics of HNC/HNSCC Head and neck cancer (HNC) originates from tissues in the oral cavity, nasal cavity, pharynx, larynx, or salivary glands, at least 90% of which is squamous cell carcinoma (HNSCC) [1]. More than 65,000 new incidences of HNC were estimated to occur in the United States in 2017 (Table 1) [2, 3]. Table 1. Overall HNC incidence and survival in United States [3].
Mefloquine hydrochloride has been used widely in the past few decades for malaria prophylaxis and treatment. However, in recent years, it has fallen out of favor due to reports of exposure being linked to numerous neuropsychiatric effects, including emotional disturbances. In this study we examined the effects of different doses (5, 25, or 100 mg/kg) of mefloquine relative to vehicle on male C57BL/6 J mice in two tests of emotional behavior, the light–dark box and the tail suspension test. It was found that mefloquine exposure reduced anxiety-linked behaviors in the light–dark box and reduced total immobility times in the tail suspension test, especially at higher doses. Our results lend support to the notion that mefloquine exposure could induce emotional disinhibition.
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