RESUMO
The Doublesex/Mab-3 Domain transcription factor DMD-10 is expressed in several cell types in C. elegans, including in the nervous system. We sought to investigate whether DMD-10 is required for normal neuronal function using behavioral assays. We found that mutation of dmd-10 did not broadly affect behavior. dmd-10 mutants were normal in several behavioral assays including a body bends assay for locomotion, egg laying, chemotaxis and response to gentle touch to the body. dmd-10 mutants did have defects in nose-touch responsiveness, which requires the glutamate receptor GLR-1. However, using quantitative fluorescence microscopy to measure levels of a GLR-1::GFP fusion protein in the ventral nerve cord, we found no evidence supporting a difference in the number of GLR-1 synapses or in the amount of GLR-1 present in dmd-10 mutants. dmd-10 mutants did have decreased responsiveness to high osmolarity, which, along with nose-touch, is sensed by the polymodal sensory neuron ASH. Furthermore, mutation of dmd-10 impaired behavioral response to optogenetic activation of ASH, suggesting that dmd-10 promotes neuronal signaling in ASH downstream of sensory receptor activation. Together our results suggest that DMD-10 is important in regulating the frequency of multiple ASH-dependent behavioral responses.
RESUMO
Anti-programmed death 1 (PD-1) immune checkpoint inhibitors (ICI) have revolutionized the treatment of advanced head and neck squamous cell carcinoma (HNSCC) but benefit only a small subset of patients. Several studies have previously assessed the predictive value of peripheral lymphocyte count for ICI therapy responses; however the optimal lymphocyte measure for the best predictive value in HNSCC is unknown. The present study examined the predictive values of multiple peripheral lymphocyte measures for anti-PD-1 ICI therapy in advanced HNSCC. Clinicopathologic data were retrospectively collected on patients with recurrent or metastatic HNSCC who had received anti-PD-1 therapy. The association between clinical outcomes and various peripheral lymphocyte count measures was analyzed, including absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratios (NLR) at baseline, week 6, and change from baseline to week 6. The primary outcome of interest was progression-free survival (PFS). A total of 108 patients with HNSCC who had received anti-PD-1 therapy were identified. The median PFS was 4.1 months. Week 6 high ALC (≥0.77) and low NLR (<6.2) were associated with a longer PFS (5.6 vs. 3.1 months, P=0.002; and 8.7 vs. 2.9 months, P=0.001, respectively). Decreased NLR during treatment was also associated with an improved PFS (6.7 vs. 2.7 months; P=0.015). Baseline lymphocyte counts and absolute lymphocyte changes during treatment did not predict ICI outcome. The present single institution retrospective study suggested that ALC and NLR values at week 6, and on-treatment NLR dynamic change have predictive value for anti-PD-1 therapy response.
RESUMO
OBJECTIVES: To examine the impact of treatment sequences of Immune checkpoint inhibitor (ICI) and cetuximab on clinical outcomes in patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Clinicopathologic data were retrospectively collected on patients with R/M HNSCC who received ICI treatment. Association between treatment sequence and clinical outcomes were assessed. RESULTS: A total of 113 patients with R/M HNSCC were analyzed. Patients who had cetuximab prior to ICI had worse overall (HR, 1.83) and progression-free survival (HR, 1.76) compare to those without prior cetuximab. Among patients who had subsequent therapy after ICI, cetuximab-based therapy was associated with a trend toward higher response rate and longer survival than non-cetuximab regimen. CONCLUSION: Our single institution analysis showed that treatment sequence of cetuximab and ICI in R/M HNSCC may affect clinical outcomes. Cetuximab prior to ICI was associated with worse outcomes while the efficacy of cetuximab may be enhanced after ICI therapy.
