Telocytes protect against lung tissue fibrosis through hexokinase 2-dependent pathway by secreting hepatocyte growth factor.

Pulmonary fibrosis (PF) is one of the common manifestations of end-stage lung disease. Chronic lung failure after lung transplantation is mainly caused by bronchiolitis obliterans syndrome (BOS) and is mainly characterized by lung tissue fibrosis. Pulmonary epithelial-mesenchymal transformation (EMT) is crucial for pulmonary fibrosis. Telocytes (TCs), a new type of mesenchymal cells, play a protective role in various acute injuries. For exploring the anti-pulmonary fibrosis effect of TCs in the BOS model in vitro and the related mechanism, rat tracheal epithelial (RTE) cells were treated with transforming growth factor-ß (TGF-ß) to simulate lung tissue fibrosis in vitro. The RTE cells were then co-cultured with TCs primarily extracted from rat lung tissue. Western blot, Seahorse XF Analysers and enzyme-linked immunosorbent assay were used to detect the level of EMT and aerobic respiration of RTE cells. Furthermore, anti-hepatocyte growth factor (anti-HGF) antibody was exogenously added to the cultured cells to explore further mechanisms. Moreover, hexokinase 2 (HK2) in RTE cells was knocked down to assess whether it influences the blocking effect of the anti-HGF antibody. TGF-ß could induce lung tissue fibrosis in RTE cells in vitro. Nevertheless, TCs co-culture decreased the level of EMT, glucose metabolic indicators (lactate and ATP) and oxygen levels. Furthermore, TCs released hepatocyte growth factor (HGF). Therefore, the exogenous addition of anti-HGF antibody in the co-culture system blocked the anti-lung tissue fibrosis effect. However, HK2 knockdown attenuated the blocking effect of the anti-HGF antibody. In conclusion, TCs can protect against lung tissue fibrosis by releasing HGF, a process dependent on HK2.

Development and Validation of PET/CT-Based Nomogram for Preoperative Prediction of Lymph Node Status in Esophageal Squamous Cell Carcinoma.

PURPOSE: This study was conducted to predict the lymph node status and survival of esophageal squamous cell carcinoma before treatment by PET-CT-related parameters. METHODS: From January 2013 to July 2018, patients with pathologically diagnosed ESCC at our hospital were retrospectively enrolled. Completed esophagectomy and two- or three-field lymph node dissections were conducted. Those with neoadjuvant therapy were excluded. The first 65% of patients in each year were regarded as the training set and the last 35% as the test set. Nomogram was constructed by the "rms" package. Five-year, overall survival was analyzed based on the best cutoff value of risk score determined by the "survivalROC" package. RESULTS: Ultimately, 311 patients were included with 209 in the training set and 102 in the test set. The positive rate of the lymph node in the training set was 36.8% and that in the test set was 32.4%. The C-index of the training set was 0.763 and the test set was 0.766. The decision curve analysis showed that it was superior to the previous methods based on lymph node uptake or long/short axis diameter or axial ratio. Risk score > 0.20 was significantly associated with 5-year, overall survival (p = 0.0015) in all patients. CONCLUSIONS: The nomogram constructed from PET-CT parameters including primary tumor metabolic length and thickness can accurately predict the risk of lymph node metastasis in ESCC. The risk score calculated by our model accurately predicts the patient's 5-year overall survival.

Neoadjuvant therapy with immunoagent (nivolumab) or placebo plus chemotherapy followed by surgery and adjuvant treatment in subjects with resectable esophageal squamous cell carcinoma: study protocol of a randomized, multicenter, double blind, phase II trial (NATION-2203 trial).

Background: Neoadjuvant chemotherapy (nCT) has been the recommended treatment for locally advanced esophageal squamous cell carcinoma (ESCC). The addition of programmed cell death protein 1 (PD-1) inhibitor to nCT may improve oncologic outcome and survival. However, high-level evidence of neoadjuvant immunotherapy (nIT) combined with nCT in locally advanced resectable ESCC patients are still lacking. Hence, we describe this randomized controlled trial in order to assess the efficacy and safety of neoadjuvant nivolumab in combination with chemotherapy for locally advanced (stage II-III) ESCC patients. Methods: This prospective, randomized, multicenter phase II trial aims to enroll 90 locally advanced (stage II-III) ESCC patients who will undergo nivolumab or placebo plus chemotherapy followed by surgery. Patients will be 2:1 randomized to nivolumab/chemo and placebo/chemo group by method of stratified randomization. In both arms, patients who have not achieved complete pathological complete response (pCR) will be administered with adjuvant nivolumab for up to 1 year. The primary endpoint is pCR rate and secondary endpoints include event-free survival (EFS), R0 resection rate, and adverse events (AEs). The safety will be evaluated by AEs, grading by Common Terminology Criteria for Adverse Events (CTCAE) 5.0 classifications. The double-blind will be maintained between subjects and investigators until the final unblinding process. Discussion: This protocol has been reviewed and approved by the Ethics Committee of Zhongshan Hospital (B2022-004R). This is the first prospective, multicenter, randomized controlled trial to compare the combination of immunotherapy and chemotherapy with standard chemotherapy in neoadjuvant treatment for ESCC, also to explore whether adjuvant immunotherapy offers additional benefit in non-pCR patients after nCT with/without immunotherapy and R0 resection. We hypothesize that the pCR rate, R0 resection rate, EFS and OS of the study group (nivolumab/chemo) is significantly better than those of control group. Registration: ClinicalTrial.gov: NCT05213312.

Single-nucleotide polymorphism rs17548629 in RIPK1 gene may be associated with lung cancer in a young and middle-aged Han Chinese population.

BACKGROUND: Genetic biomarkers of lung cancer (LC) susceptibility may provide a basis for treatment and prevention. This study analyzed an association between SNPs (single nucleotide polymorphisms) in the complementary region of the 3'-UTR (3' untranslated region) of microRNAs of the gene RIPK1 (receptor-interacting serine/threonine-protein kinase 1) and LC among an adult Han Chinese population aged younger than 60 years. Also explored the effect of regulation of the RIPK1 gene via rs17548629 and microRNA-1197 on the occurrence of LC. METHODS: RIPK1 variants (rs17548629, rs77736895) were determined in a population of 571 adults (younger than 60 years) with LC, and 609 gender- and age-matched healthy individuals. Bioinformatics methods predicted the microRNAs bound to rs17548629. Dual luciferase reporter assay was performed to confirm the presence of both rs17548629 and the predicted microRNA. RESULTS: A mutation (T) of rs17548629 was associated with an increased risk for LC in this population under the codominant and recessive genetic models. The risk of lung adenocarcinoma in rs17548629 mutant carriers was 1.769-fold higher than that of the wildtype. In vitro, the luciferase activity of co-transfected mutant psiCHECK2-RIPK1 and microRNA-1197 mimics was less than that of the group transfected with microRNA-1197 mimics only. Factorial analysis indicated interactions between microRNA-1197 mimics and genotypes of rs17548629. CONCLUSION: A mutation (T) of rs17548629 may increase the risk of LC/lung adenocarcinoma in adult Han populations younger than 60 years. When carrying the T allele, rs17548629 may be the target of hsa-miR-1197. This mutation may affect transcriptional level of the RIPK1, thereby promoting the occurrence of LC.