CTLA-4 and its inhibitors in esophageal cancer: efficacy of therapy and potential mechanisms of adverse events.

Esophageal cancer is one of the most prevalent diseases in the world, and its prognosis remains poor. Surgery, chemotherapy, and radiotherapy are the most common treatment strategies for esophageal cancer. Although these conventional treatment methods are sometimes beneficial, patients with esophageal cancer still have a high risk of local relapse and metastasis. Thus, novel and effective therapies are needed. Immune checkpoint inhibitors are a type of immunotherapy being studied as a treatment for patients with advanced cancers, and strategies using such inhibitors have rapidly progressed to be recognized as transformative treatments for various cancers in recent years. Immune checkpoint inhibitors combined with chemotherapy or radiotherapy have become the first-line and second-line treatment strategies for advanced esophageal cancer. In addition, immune checkpoint inhibitors have also been recognized as another option for patients with terminal esophageal cancer who cannot benefit from chemotherapy, and they even have potential benefits as a novel neoadjuvant treatment option for locally advanced esophageal cancer. Currently, there are two types of immune checkpoint inhibitors commonly applied in clinical practice: immune checkpoint inhibitors targeting programmed death 1/programmed cell death ligand 1 and immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein 4. However, cytotoxic T-lymphocyte-associated protein 4 immune checkpoint inhibitors are rarely used compared with programmed death 1/programmed cell death ligand 1 inhibitors in esophageal cancer and other cancers, and the clinical benefit is unclear. We analyzed and summarized the efficacy and safety of cytotoxic T-lymphocyte-associated protein 4 immune checkpoint inhibitors in the treatment of esophageal cancer. Due to the lack of clinical applications, it is expected that cytotoxic T-lymphocyte-associated protein 4 immune checkpoint inhibitors in combination with other treatments may provide superior benefits and improve the prognosis of patients with esophageal cancer.

Clinical significance of high mobility group box 1/toll-like receptor 4 in obese diabetic patients.

High mobility group box 1 (HMGB1) is an alarmin that may link to obesity and type 2 diabetes mellitus (T2DM). The present study analyzed the correlation between HMGB1/ Toll-like receptor 4 (TLR4) and certain biochemical parameters in obese (OB) diabetic patients. 40 normal glucose tolerant subjects (NGT) and 40 patients with newly diagnosed T2DM were enrolled. All patients were further divided into non-obese NGT (NGT-NOB), obese NGT (NGT-OB), non-obese T2DM (T2DM-NOB) and obese T2DM (T2DM-OB) groups according to body mass index (BMI).The levels of HMGB1 in serum were quantified using ELISA, whereas the mRNA expression levels of TLR4 in peripheral blood mononuclear cells were assessed using reverse transcription-quantitative PCR. The results suggested that the levels of HMGB1 and TLR4 were higher in NGT-OB and T2DM-NOB groups compared with those in NGT-NOB group. Similarly, the levels of these two markers were higher in T2DM-OB group compared with those in NGT-OB group. Correlation analysis indicated that the levels of HMGB1 and TLR4 were positively correlated with triglyceride (TG), fasting plasma glucose (FPG) levels and BMI, whereas a negative correlation between HMGB1 and high density lipoprotein (HDL) was noted. Linear regression analysis suggested that HMGB1 was associated with FPG and TG levels, whereas TLR4 was strongly associated with TG levels and BMI. The results demonstrated that the expression levels of HMGB1 and TLR4 in patients with T2DM or obesity were increased, which were associated with glycolipid metabolism disorders. Therefore, the HMGB1/TLR4 may serve a role in inflammatory process associated with obesity and T2DM.

Effects of IL-33 on 3T3-L1 cells and obese mice models induced by a high-fat diet.

Obesity is a syndrome that attributes to many factors such as genetics, diet, lifestyle and environment, which includes an imbalance of immune regulation. IL-33, as a new member of the IL-1 family, is classically associated with type 2 immune responses. Here, IL-33 was investigated for its ability to optimize lipid aggregation and ameliorate the inflammatory response in obesity. In vitro experimental results showed that, compared with the induction group, the treatment with 30 ng/mL IL-33 displayed a reduction in the number of lipid droplets. The expression levels of AceCS1 and PPARγ also decreased in the 30 ng/mL IL-33 group compared to the induction group. For confirmation in vivo, three groups of C57BL/6 mice were treated for 14 weeks: mice in control were fed with a normal diet; mice in the HFD and IL-33 groups were fed with a high-fat diet (HFD) and with sterile PBS or recombinant IL-33, respectively. Liver, muscle, spleen and four types of adipose tissue, as well as serum, were collected for further testing. Our data demonstrated that after 4-week treatment with recombinant IL-33, metabolic parameters in mice were improved significantly (visceral fat weight, glucose and insulin tolerance, liver steatosis, expression of lipid synthesis index and inflammatory response). Moreover, IL-33 treatment regulated the original distribution of IL-33 among different tissues. Hence, IL-33 modulated lipid metabolism and inflammatory response in obesity, which would be a novel therapeutic target for obesity and related metabolic diseases.