c-Met is a chimeric antigen receptor T-cell target for treating recurrent nasopharyngeal carcinoma.

BACKGROUND AIMS: Radiation therapy is the standard treatment for patients with nasopharyngeal carcinoma (NPC), but relapse occurs in 10% to 20% of patients. The treatment of recurrent nasopharyngeal carcinoma (rNPC) remains challenging. Chimeric antigen receptors (CAR)-T-cell therapy has achieved good outcomes in the treatment of leukemia and seems to be a promising therapeutic strategy for solid tumors. c-Met has been found to be highly expressed in multiple cancer types, and the activation of c-Met leads to the proliferation and metastasis of cancer cells. However, the expression of c-Met in rNPC tissues and whether it can be used as a target for CAR-T therapy in rNPC remain to be investigated. METHODS: We detected the expression of c-Met in 24 primary human rNPC tissues and three NPC cell lines and constructed two different antibody-derived anti-c-Met CARs, namely, Ab928z and Ab1028z. To estimate the function of these two different c-Met-targeted CAR-T cells, CD69 expression, cytotoxicity and cytokine secretion of CAR-T cells were assessed after coculture with target cells. A cell line-derived xenograft mouse model also was used to evaluate these two anti-c-Met CAR-T cells. Furthermore, we determined whether combination with an anti-EGFR antibody could promote the antitumor effect of CAR-T cells in a patient-derived xenograft mouse model. RESULTS: High c-Met expression was detected in 23 of 24 primary human rNPC tissues by immunohistochemistry staining and in three NPC cell lines by flow cytometry. Ab928z-T cells and Ab1028z-T cells showed significantly upregulated expression of CD69 after coculture with targeted cells. However, Ab1028z-T cells showed superior cytokine secretion and antitumor activity. Furthermore, Ab1028z-T cells effectively suppressed tumor growth compared with control CAR-T cells, and the combination with nimotuzumab further enhanced the tumor-clearing ability of Ab1028z-T cells. CONCLUSIONS: We found that c-Met is highly expressed in rNPC tissues and confirmed its potential as a CAR-T target for rNPC. Our study provides a new idea for the clinical treatment of rNPC.

Effects of Swallowing Rehabilitation Training with a Balloon Dilation Therapy on the Deglutition Function and Quality of Life of Patients with Dysphagia after Radiotherapy for Nasopharyngeal Carcinoma.

Objective: The aim of this study is to investigate the effects of swallowing rehabilitation training with a balloon dilation therapy on the deglutition function and quality of life of patients with dysphagia after radiotherapy for nasopharyngeal carcinoma (NPC). Methods: The study was a retrospective study. The data of the 100 patients with dysphagia after NPC radiotherapy in our hospital between April 2021 and April 2022 were retrospectively analyzed. The patients were separated into the control group (n = 50) and experimental group (n = 50) according to their different treatments that were balloon dilation for the former and balloon dilation with swallowing rehabilitation training for the latter. The deglutition function, which was comprehensively evaluated by Kubota's water swallow test and assessments of penetration/aspiration and pharyngeal residue, and quality of life were compared between the two groups. Results: The scores of Kubota's water swallow test, penetration aspiration scale (PAS), and Yale pharyngeal residue severity rating scale (YPR-SRS) in the experimental group after treatment were (2.04 ± 0.66), (2.92 ± 1.07), and (2.42 ± 0.90), respectively, which were remarkably lower than (2.58 ± 0.78), (4.38 ± 1.51), and (2.78 ± 0.86) in the control group, with distinct differences in the data between both the groups (P < 0.05). The quality of life of patients in the experimental group was distinctly better than that in the control group (P < 0.001). Conclusion: Swallowing rehabilitation training in combination with a balloon dilation therapy can improve the deglutition function in patients with dysphagia after NPC radiotherapy as well as their quality of life, with a clinical application value.

Activation of endothelin-1 receptor signaling pathways is associated with neointima formation, neoangiogenesis and irreversible pulmonary artery hypertension in patients with congenital heart disease.

BACKGROUND: It is unclear why some patients, who undergo complete repair or palliative surgery for congenital heart disease (CHD), still develop irreversible pulmonary artery hypertension (PAH). There is no consensus to preoperationally assess the reversible and irreversible pulmonary vasculopathy seen in PAH. METHODS AND RESULTS: The peri-operative pulmonary hemodynamic data of 16 CHD patients (reversible PAH, n = 6; irreversible PAH, n = 10) were analyzed. The lung biopsies were also performed during surgery for defining histopathological characteristics as well as immunohistochemical expression of endothelin-1 (ET-1), endothelin-1 receptors (ETR), and its downstream signaling markers in the small pulmonary arteries and arterioles. Neointimal formation and neoangiogenesis was characterized by increased intimal layer immunoreactivity for α-SMA, Factor VIII, CD34, and VEGF. Neointimal formation was found in 90% of patients and neoangiogenesis was found in 80% of patients with irreversible PAH. Neither was present in the reversible PAH group and the control group. Expression of ET-1 and ETR in the neointimal layer of the pulmonary arterioles was upregulated in irreversible PAH, and immunoreactivity of phospho-Akt, phospho-ERK1/2, and phospho-mTOR was also increased in irreversible PAH. CONCLUSIONS: Increased expression of ET-1, ETR, and activation of signaling pathways were observed in the pulmonary arteries and arterioles of irreversible PAH patients associated with CHD. Activation of these pathways might in turn lead to neointimal formation and neoangiogenesis and thus might contribute to irreversible pulmonary vascular abnormalities.

[Overexpression of endothelin-1 induces hypertrophy of rat pulmonary arterial microvascular smooth muscle cells via Akt/mTOR pathway].

OBJECTIVE: To investigate the effects of endothelin-1 (ET-1) overexpression on hypertrophy of the rat pulmonary arterial microvascular smooth muscle cells (RPMCs) in vitro. METHODS: Lung tissue perfusion method was used to obtain the primary RPMCs, and then the cells were transiently transfected with ET-1 plasmids or empty vectors via Lipofectamine. Flow cytometry was used to determine the distributions of the cell cycle and cell size of RPMCs. Immunofluorescence staining and Western blotting were used to determine the level of alpha-smooth muscle actin. The ratio of the protein/DNA of the transfected RPMCs was also calculated. Western blotting was used to examine the levels of phosphorylations of protein kinase B/Akt, mTOR, and ERK1/2. RESULTS: Primary RPMCs were isolated successfully. Overexpression of ET-1 resulted in a significant increase in total protein synthesis, expression of alpha-SMA, as well as increased cell size. Western blotting results showed that overexpression of ET-1 resulted in increased phosphorylation of Akt, mTOR and a decreased phosphorylation of ERK1/2 in RPMC. CONCLUSIONS: ET-1 overexpression induces RPMC hypertrophy and activation of Akt/PKB-mTOR pathway may be involved in the mechanism, with important implications for the pathogenesis of vascular remodeling in pulmonary arterial hypertension.

[Endothelin-1 overexpression inhibits rat pulmonary arterial microvascular smooth muscle cell apoptosis via Akt/PKB pathway].

OBJECTIVE: To investigate the effects of endothelin-1 (ET-1) overexpression on apoptosis of the rat pulmonary arterial microvascular smooth muscle cells (RPMC) in vitro. METHODS: Primary RPMC obtained from the pulmonary artery and lung microvasculature were identified by immunofluorescence staining and electron microscope technique. The RPMC was transient transfected with the pMEXneo-ET1 and pCDNA5-FRT-TO-ET1-3'UTR plasmids as well as the empty vector respectively via lipofectamine. Flow cytometry was used to assess the cell cycle and apoptosis of RPMC. Akt and Caspase-3 expressions were detected by Western blot and real time RT-PCR. RESULTS: The mRNA of ET(A) expression was significantly higher than that of ET(B) receptor in primary RPMC. Flow cytometry analysis revealed significantly reduced apoptosis in ET-1 transfected RPMC compared to that in vehicle transfected RPMC. Overexpression of ET-1 in RPMC also significantly increased the phosphorylation of Akt and reduced the cleaved Caspase-3 expression. CONCLUSIONS: Overexpression of the ET-1 inhibited RPMC apoptosis and activated Akt/PKB-Caspase-3 signaling pathway, which might be responsible for ET-1 induced the pulmonary microvascular arteries remodeling.

[Security evaluation of bupivacaine, ropivacaine combined with fentanyl in postoperative continuous epidural analgesia].

OBJECTIVE: To investigate the effects, side-effects and security of bupivacaine, ropivacaine combined with fentanyl in postoperative continuous epidural analgesia. METHODS: A total of 1 600 postoperative continuous epidural analgesia patients receiving different agents in SICU were divided into two groups: 0.1% bupivacaine +5 microg/ml fentanyl group (group B, n = 920) and 0.2% ropivacaine +2 microg/ml fentanyl group (group R, n = 680). The effects (visual analog-scale score and content to analgesia), side effects were analyzed retrospectively in the two groups. RESULTS: Compared with group B, patients in group R had higher analgesia contentment (P < 0.05), but no difference in visual analog-scale score was found in the two groups. The incidences of urinary retention, nausea and vomiting, skin itching in group B were significantly higher than those in group R (P < 0.05). In each group, patients over sixty had higher ratio of hypotension than those under sixty (P < 0.05); The female patients had a higher incidence of nausea and vomiting than male patients (P < 0.05); The incidence of debility and numbness of lower limbs in patients with lumbar segments epidural analgesia was higher than those with thoracic analgesia (P < 0.05). CONCLUSIONS: 0.1% bupivacaine +5 microg/ml fentanyl and 0.2% ropivacaine +2 microg/ml fentanyl can provide adequate pain relief in postoperative continuous epidural analgesia, and 0.2% ropivacaine +2 microg/ml fentanyl comes with less side effects. The incidence of complication is related with analgesics, age, gender and the position of epidural puncture.