A recently discovered human glycoprotein, chitinase 3-like 1 (Chi3L1), may play a role in inflammation, tissue remodeling, and visceral fat accumulation. We hypothesize that Chi3L1 gene expression is important in the development of hepatic insulin resistance characterized by the generation of pAKT, pGSK, and pERK in wild type and Chi3L1 knockout (KO) murine liver following insulin stimulation. The Chi3L1 gene and protein expression was evaluated by Real Time PCR and ELISA; lipid accumulation in hepatocytes was also assessed. To alter Chi3L1 function, three different anti-Chi3L1 monoclonal antibodies (mAbs) were administered in vivo and effects on the insulin signaling cascade and hepatic lipid deposition were determined. Transmission of the hepatic insulin signal was substantially improved following KO of the CHi3L1 gene and there was reduced lipid deposition produced by a HFD. The HFD-fed mice exhibited increased Chi3L1 expression in the liver and there was impaired insulin signal transduction. All three anti-Chi3L1 mAbs partially restored hepatic insulin sensitivity which was associated with reduced lipid accumulation in hepatocytes as well. A KO of the Chi3L1 gene reduced lipid accumulation and improved insulin signaling. Therefore, Chi3L1 gene upregulation may be an important factor in the generation of NAFLD/NASH phenotype.

PURPOSE: Neoadjuvant chemotherapy (NAC) is increasingly being considered over standard upfront surgery followed by adjuvant chemotherapy for locally advanced colon cancer. Studies have been underpowered to look at the effect of NAC on overall survival (OS) in individual clinical T stages. METHODS: A nationwide retrospective analysis using the National Cancer Database from 2010 to 2020 to evaluate patients with clinical stage T3-4, N0-2, M0 colon adenocarcinomas in line with the FOxTROT trial. Cox proportional hazards model was used to evaluate the effect of NAC approach compared with upfront surgery on OS. Clinical and pathological T stages were compared among those who underwent upfront surgery to evaluate the accuracy of clinical T staging. RESULTS: A total of 60,557 patients were identified—2,313 patients undergoing NAC and 58,245 undergoing upfront surgery. In the past decade, use of NAC increased from 1.73% to 12.13%. In our multivariable survival analysis combining clinical T3 and T4 patients, we observed a worse OS in the NAC group (hazard ratio [HR], 1.16 [95% CI, 1.07 to 1.26]). We found no OS benefit for patients undergoing NAC approach for clinical stage T3 (HR, 1.13 [95% CI, 0.99 to 1.28]) but found a significant OS benefit for patients undergoing NAC approach for clinical stage T4 (HR, 0.85 [95% CI, 0.77 to 0.95]). DISCUSSION: Our analysis demonstrated OS benefit of the NAC approach in T4 colon adenocarcinoma but not in T3. This study highlights the importance of evaluating the survival benefit of NAC separately for T3 and T4 colon adenocarcinoma in future studies.