CRISPR/Cas9-mediated PD-1 disruption enhances human mesothelin-targeted CAR T cell effector functions.

The interaction between programmed cell death protein 1 (PD-1) on activated T cells and its ligands on a target tumour may limit the capacity of chimeric antigen receptor (CAR) T cells to eradicate solid tumours. PD-1 blockade could potentially enhance CAR T cell function. Here, we show that mesothelin is overexpressed in human triple-negative breast cancer cells and can be targeted by CAR T cells. To overcome the suppressive effect of PD-1 on CAR T cells, we utilized CRISPR/Cas9 ribonucleoprotein-mediated editing to disrupt the programmed cell death-1 (PD-1) gene locus in human primary T cells, resulting in a significantly reduced PD-1hi population. This reduction had little effect on CAR T cell proliferation but strongly augmented CAR T cell cytokine production and cytotoxicity towards PD-L1-expressing cancer cells in vitro. CAR T cells with PD-1 disruption show enhanced tumour control and relapse prevention in vivo when compared with CAR T cells with or without αPD-1 antibody blockade. Our study demonstrates a potential advantage of integrated immune checkpoint blockade with CAR T cells in controlling solid tumours and provides an alternative CAR T cell strategy for adoptive transfer therapy.

[Clinical analysis of 19 cases of esthesioneuroblastoma under classic surgical approaches and surgical approaches with the assistant of nose endoscope].

OBJECTIVE: To summarize the curative effect and esthesioneuroblastoma (ENB) by classic surgical approaches and surgical approaches with the assistant of nose endoscope. METHOD: A retrospective review was conducted in 19 cases treated from 1980 to 2000. Ten cases were treated by classical surgical approaches. Tumors in 4 patients (According to the Kadish system, stage A, 3 cases; stage B, 1 case) were removed via a transnasal approach, 6 patients (stage B, 5 cases; stage C, 1 case) were performed by lateral rhinotomy. After 1995, 9 cases (stageA, 2 case; stageB, 5 cases; stageC, 2 cases) received surgical resection with nasale endoscope. All of the patients were conducted radiation after operation. RESULT: The 5-year survival rate for the classic procedure and the surgical procedure with the assistant of endoscope were 50.0%, 88.9%, respectively. And the local recurrence rates were 50.0%, 33.3%, respectively (had no statistical significance). And the mean recurrent time were 5.2 months, 16 months, respectively. With the assistant of endoscope, the recurrent time was significant retarded. CONCLUSION: There are better illumination and better operation field during the surgical operation with the assistant of endoscope. And the tumors are more likely resected entirely and the tumor recurrent time could be deferred.

[Reconstruction of laryngotracheal stenosis with hyoid graft and pedicle sternohyoid muscle flaps].

OBJECTIVE: To evaluate the possibility and reliability of hyoid graft and pedicle sternohyoid muscle flaps in the reconstruction of laryngotracheal stenosis. METHOD: Using the single or double pedicle sternohyoid muscle flaps and hyoid graft, we repaired laryngotracheal stenosis. RESULT: In all 21 cases with laryngotracheal stenosis, 16 cases were cured after one surgical procedure, and 3 cases were cured after two times of surgical procedures, and 19 cases were decannulated, but one case was failure, and one case was lost visiting. CONCLUSION: The hyoid sternohyoid graft transfer method was convenient, slightly damaging, and had good supporting effects and high survival rate in the reconstruction of laryngotracheal stenosis.

[Diagnose and treatment of severe obstructive sleep apnea hypopnea syndrome].

OBJECTIVE: To explore the diagnose and treatment of severe OSAHS with distinction of different extent. METHOD: All 256 severe OSAHS patients were divided into two groups according to sleep apnea hypopnea index (AHI): group one (severe group), 40 < AHI < 65; group two (extra severe group), AHI > or = 65. All patients were underwent CPAP treatment for at least one week before modified UPPP in general anesthesia. UPPP and (or) nasal septum plasty or partial inferior turbinectomy were operated in one stage if tracheotomy was conducted. If tracheotomy were not conducted, the patient was only accepted UPPP under general anesthesia. The other operations to remove the multi block factors were operated in local anesthesia. RESULT: In 198 group one patients, there were 169 patients accepted UPPP in general anesthesia without tracheotomy, the other 29 patients were conducted with tracheotomy. The tracheotomy rate was 14.6%. The total effective cure rate was 85.9%. In all 58 group two patients, tracheotomy were conducted, and the total effective cure rate was 63.8%. The complication rate of all the two groups' patients was 3.5%. After three weeks,the uvulas decurtated from(4.89 +/- 0.58) cm to (3.12 +/- 0.46)cm. CONCLUSION: It is important to divide the severe OSAHS patients into severe group and extra severe group because the treatments were different. Not all the severe OSAHS patients need tracheotomy. There were advantages to retain the uvula in UPPP and patients' life quality was improved with uvula reserved.