Purpose: Chemoresistance in small-cell lung cancer (SCLC) is reportedly attributed to the existence of resistant cancer stem cells (CSC). Studies involving CSC-specific markers and related mechanisms in SCLC remain limited. This study explored the role of the voltage-dependent calcium channel a2d1 subunit as a CSC marker in chemoresistance of SCLC, and explored the potential mechanisms of a2d1-mediated chemoresistance and strategies of overcoming the resistance. Experimental Design: a2d1-positive cells were identified and isolated from SCLC cell lines and patient-derived xenograft (PDX) models, and CSC-like properties were subsequently verified. Transcriptome sequencing and Western blotting were carried out to identify pathways involved in a2d1mediated chemoresistance in SCLC. In addition, possible interventions to overcome a2d1-mediated chemoresistance were examined. Results: Different proportions of a2d1 þ cells were identified in SCLC cell lines and PDX models. a2d1 þ cells exhibited CSClike properties (self-renewal, tumorigenic, differentiation potential, and high expression of genes related to CSCs and drug resistance). Chemotherapy induced the enrichment of a2d1 þ cells instead of CD133 þ cells in PDXs, and an increased proportion of a2d1 þ cells corresponded to increased chemoresistance. Activation and overexpression of ERK in the a2d1-positive H1048 cell line was identified at the protein level. mAb 1B50-1 was observed to improve the efficacy of chemotherapy and delay relapse as maintenance therapy in PDX models. Conclusions: SCLC cells expressing a2d1 demonstrated CSClike properties, and may contribute to chemoresistance. ERK may play a key role in a2d1-mediated chemoresistance. mAb 1B50-1 may serve as a potential anti-SCLC drug. Clin Cancer Res; 24(9); 2148-58. Ó2018 AACR.

The associations between serum total bilirubin (sTB) levels, inflammatory marker levels, and disease activity are not well understood in patients with inflammatory bowel disease (IBD). The present study investigated the association between sTB levels and disease activity in patients with IBD. We conducted a retrospective study with a total of 242 consecutive patients with Crohn’s disease (CD) and 211 consecutive patients with ulcerative colitis (UC). The Crohn’s Disease Activity Index (CDAI) score was used to assess disease activity in patients with CD and the Mayo score of patients with UC. 255 clinically healthy subjects comprised the control group, which come from the same geographic area as the IBD group. We retrieved the clinical and laboratory parameters of patients with IBD from the medical records. Patients with IBD displayed significantly lower sTB levels than controls. sTB levels were negatively associated with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fecal calprotectin (FC), and hemoglobin (Hb) levels in patients with IBD. Additionally, there was a negative association between sTB levels and the CDAI score of patients with CD. sTB levels were also negatively associated with the Mayo score of patients with UC. IBD patients had lower sTB levels when compared with controls, and there was a negative correlation between sTB levels and disease activity in patients with IBD. Increased reactive oxygen species production in IBD is likely to be responsible for increased consumption of bilirubin in patients with IBD, leading to further intestinal injury. Reducing oxidative stress may be therapeutic for these patients.

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