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Loss of phosphatase and tensin homolog (PTEN) has been linked to an immunosuppressive tumor microenvironment, but its underlying mechanisms remain largely enigmatic. Here, we report that PTEN can be secreted by the transmembrane emp24 domain-containing protein 10 (TMED10)-channeled protein secretion pathway. Inhibiting PTEN secretion from tumor cells contributes to immunosuppression and impairs the tumor-suppressive role of PTEN, while intratumoral injection of PTEN protein promotes antitumor immunity and suppresses tumor growth in mice. Mechanistically, extracellular PTEN binds to the plexin domain-containing protein 2 (PLXDC2) on macrophages, triggering subsequent activation of JAK2-STAT1 signaling, which switches tumor-associated macrophages (TAMs) from the immunosuppressive to inflammatory phenotype, leading to enhanced activation of CD8 + T and natural killer cells. Importantly, PTEN treatment also enhances the therapeutic efficacy of anti-PD-1 treatment in mice and reverses the immune-suppressive phenotype of patient-derived primary TAMs. These data identify a cytokine-like role of PTEN in immune activation and tumor suppression and demonstrate the therapeutic potential for extracellular administration of PTEN in cancer immunotherapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Krüppel-like factor 17 (KLF17) has been reported to be involved in invasion and metastasis suppression in lung cancer, but the molecular mechanisms underlying the anti-invasion and anti-metastasis roles of KLF17 in lung cancer are not fully illustrated. Here, we showed that KLF17 inhibited the invasion of A549 and H322 cells; the anti-invasion effect of KLF17 was associated with the suppression of urokinase plasminogen activator (uPA/PLAU) expression. KLF17 can bind with the promoter of uPA and inhibit its expression. Enforced expression of uPA abrogated the anti-invasion effect of KLF17 in A549 and H322 cells. In addition, immunohistochemistry staining showed that the protein expression of KLF17 was negatively correlated with that of uPA in archived samples from patients with lymph node metastasis of lung adenocarcinoma (rho = -0.62, P = 0.01). The mutually exclusive expression of KLF17 with uPA could predict lymph node metastasis for lung adenocarcinoma (AUC = 0.758, P = 0.005). Enforced expression of KLF17 inhibited the expression of phosphorylated Src and phosphorylated p38/MAPK in A549 and H322 cells. The invasiveness of the cells were suppressed by treating with sb203580 (p38/MAPK inhibitor) or HY-13805 (PP2, Src inhibitor). furthermore, p38/MAPK inhibition could block the KLF17-induced reduction of p-p38/MAPK and uPA, and Src inhibition enhanced the KLF17-induced suppression of p-Src and uPA in A549 and H322 cells. In conclusion, our study indicated that KLF17 suppressed the uPA-mediated invasion of lung adenocarcinoma. The Src and p38/MAPK signaling pathways were suggested as mediators of KLF17-induced uPA inhibition, thus providing evidence that KLF17 might be a potential anti-invasion candidate for lung adenocarcinoma.

Objective: To explore the possibilities and efficiency of Sigma covered stents for the treatment of tracheoesophageal fistula (TEF)., Methods: Between 2006 and 2009, 10 Sigma covered mental stents had been placed by guidance of bronchoscopy and/or fluoroscopy in 8 patients with 9 tracheoesophageal fistulas. Among them, 7 fistulas were caused by cancer and 2 by mechanical damage. Seven fistulas were located in lower part of trachea and 1 each in the middle and upper parts., Results: Six Y-shaped, 2 L-shaped and 2 I-shaped stents were placed respectively in 8 patients with 9 TEFs. All the TEFs were effectively sealed by the stents except for 1 massive lower and 1 upper fistulas. One mechanical fistula was cured within 1 year of stent placement. The mean survival period of all patients was 8 months., Conclusion: By sealing the fistula with a Sigma covered stent, severe respiratory infection may be successfully controlled in patients with TEFs with a major improvement of quality of life.

Objective: To study the expression of leukemia inhibitory factor (LIF) and neurokinin receptors (NKR) in the lungs of asthmatic rats, and to evaluate the role of LIF in airway neurogenic inflammation., Methods: Twenty-four Wistar rats were randomly divided into a control group (group A, n = 8), an asthma group (group B, n = 8) and a dexamethasone treated group (group C, n = 8). The rat asthmatic model was made by intraperitoneal injection and nebulized aspiration of ovalbumin (OVA) at the concentrations of 10% and 1% respectively. Expression levels of lung LIF, NK-1R and NK-2R were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot two weeks after challenge, and the localization of NK-1R was determined by immunohistochemistry., Results: After challenge, the expressions of lung LIF mRNA in group A, B and C were 0.240 +/- 0.020, 0.510 +/- 0.130, 0.180 +/- 0.050, and protein levels were 23 110 +/- 8 018, 40 832 +/- 12 964, 16 160 +/- 2 108 respectively. The expressions of lung NK-1R mRNA in group A, B and C were 0.240 +/- 0.020, 1.040 +/- 0.480, 0.170 +/- 0.040, and protein levels were 16 538 +/- 4 342, 32 292 +/- 4 564, 15 018 +/- 1 488 respectively. The mRNA and protein levels of LIF and NK-1R in group B were significantly elevated as compared with group A and C (all P < 0.01). The expressions of lung NK-2R mRNA in group A, B and C were 0.240 +/- 0.040, 0.200 +/- 0.030 and 0.210 +/- 0.040, and no difference was found among three groups (all P > 0.05). In group B, there was a positive correlation between LIF and NK-1R at mRNA (r = 0.850, P < 0.01) and protein (r = 0.868, P < 0.01) levels respectively. NK-1R immunoreactivity was observed primarily in bronchial epithelial cells., Conclusion: LIF and NK-1R were excessively expressed and closely correlated in lungs of the rat asthmatic model, suggesting that LIF may be involved in modulating airway neurogenic inflammation.

Objective: To explore the spectrum and frequency of causes for chronic cough in Chinese patients., Methods: 86 patients with chronic cough were enrolled in the study. The diagnostic procedure was based on the anatomical protocol for diagnosing chronic cough designed by Irwin, and additional cytological assay was performed for sputum induced by hypertonic saline aerosol inhalation. The efficacy of therapy specific to the diagnosis was evaluated., Results: Definite diagnosis was made in 77 (89.5%) out of the 86 patients with chronic cough. The most common causes included cough variant asthma (CVA) (24/86, 27.9%), postnasal drip syndrome (PNDs) (22/86, 25.6%), eosinophilic bronchitis (EB) (13/86, 15.1%), and gastroesophageal reflux (GER) (12/86, 14.0%). After active management based on the diagnosis, cough improved in 72 patients (93.5%)., Conclusions: In addition to CVA, PNDs and GER, eosinophilic bronchitis is also an important cause of chronic cough. A positive response to the specific therapy is essential to a definite diagnosis.

Objective: To investigate the clinical features, diagnosis and management of gastroesophageal reflux induced cough (GERC)., Methods: The continuous ambulatory esophageal pH measurement was performed for 24 hour in 41 cases with chronic cough who had normal chest roentgenographic presentation, negative histamine provocation test and no abnormality of nasal cavity. The symptom association probability (SAP) was adopted to analyze the correlation of cough with gastroesophageal reflux. The anti-reflux treatment was given for 12 weeks to those patients with Demeester score >or= 14.72 and/or SAP >or= 75%., Results: Twenty six out of 41 cases were diagnosed as patients with gastroesophageal reflux. The cough was completely cured in 12 cases after antireflux treatment. The SAP of cough in this cured group (proximal probe 0.75 +/- 0.21, distal probe 0.91 +/- 0.12, respectively) was significantly higher than that of patients who failed in response to antireflux treatment (proximal probe 0.36 +/- 0.31, distal probe 0.47 +/- 0.30, respectively, P < 0.05)., Conclusion: The gastroesophageal reflux may be an independent factor which could induce chronic cough. Not only the frequency and severity of gastroesophageal reflux but also the SAP were helpful in making the diagnosis of GERC. Satisfied effect was achieved after sufficient anti-reflux treatment in patients with GERC.

Objective: To study the clinical features and airway inflammation in eosinophilic bronchitis (EB) and the treatment outcomes., Methods: Irwin's anatomic protocol for diagnosing chronic cough was used in 86 patients with chronic cough, and induced sputum by hypertonic saline aerosol inhalation was performed. Differential cell counts were performed in induced sputum, and eosinophilic cationic protein (ECP) was measured with fluoroimmunoassay, while interleukin-8 (IL-8) was measured with enzyme-linked absorbed immunoassay. EB was diagnosed according to Gibson's criteria and treated with inhaled budesonide 200 - 400 micro g twice daily for four weeks, and in some patients oral prednisone 10 - 15 mg/d or methyl-prednisone 8 - 12 mg/d was given for one week., Results: 13 (15%) out of 86 patients with chronic cough were diagnosed as having EB. Dry cough was the major compliant and all had normal lung function with negative histamine provocation test. The Eos count was 0.1862 +/- 0.1632 and the concentration of ECP (2.53 +/- 2.07) mg/L in induced sputum were significant higher in patients with EB as compared with those normal subjects (P < 0.01). The cough disappeared in all patients at the end of one week of inhaled or orally administered corticosteroids., Conclusion: EB, an eosinophilic airway inflammation, is one of important causes of chronic cough and responds well to corticosteroid therapy.