Bing Xia

The integrity of the alveolar epithelial barrier is fundamental to pulmonary homeostasis, yet the molecular regulators governing its tight junction (TJ) dynamics remain incompletely understood. Here, we uncover a critical, non-canonical function for FGFR1 as a master regulator of TJ homeostasis. We demonstrate that the RET inhibitor pralsetinib (Pral) induces fatal interstitial lung disease by inhibiting FGFR1, not RET, leading to the selective loss of occludin (OCLN). This disruption stems from transcriptional repression, mediated by the transcription factor CREB1. By integrating in vitro and in vivo studies, including lung epithelial-specific Fgfr1-knockout mice, we confirm that Fgfr1 deficiency alone is sufficient to disrupt tight junctions, reduce OCLN expression, and trigger spontaneous lung injury. Our findings establish the FGFR1-CREB1-OCLN axis as a central regulator of TJ integrity, offering new therapeutic perspectives for lung diseases associated with TJ dysfunction.

Immune checkpoint inhibitors (ICIs) therapy has revolutionized the treatment patterns of non-small cell lung cancer (NSCLC). However, patients treated with ICIs may experience immune-related adverse events (irAEs). Markers that could predict the onset of irAEs are still unclear. Here, we report the possible correlation of baseline peripheral lymphocytes with irAEs and clinical outcomes in advanced NSCLC patients receiving ICIs. A total of 109 advanced NSCLC patients treated with ICIs from April 2017 to January 2021 were analyzed retrospectively. Logistic and Cox regression analyses was applied to evaluate independent risk factors for irAEs, progression-free survival (PFS), and overall survival (OS). Among these patients, 55 (50.5%) patients experienced irAEs. The level of CD8⁺ T lymphocytes at baseline was the independent risk factor for the onset of irAEs (p = 0.008). A higher level of CD8⁺ T lymphocytes was associated with longer PFS (11.0 months vs. 3.0 months, p < 0.001) and OS (27.9 months vs. 11.7 months, p = 0.014). Furthermore, patients who had higher baseline CD8⁺ T lymphocytes and experienced irAEs had a longer PFS (18.4 months vs. 2.2 months, p < 0.001) and OS (32.8 months vs. 9.0 months, p = 0.001) than those who had lower CD8+ T lymphocytes and no irAEs. Our study highlights the value of baseline peripheral CD8⁺ T lymphocytes as a predictive factor for irAEs in advanced NSCLC patients receiving ICIs. In addition, patients who have higher baseline CD8⁺ T lymphocytes and experience irAEs would have a superior PFS and OS.

Aims: Radiation therapy is used as the primary treatment for lung cancer. Unfortunately, radiation resistance remains to be the major clinic problem for lung cancer patients. Lysimachia capillipes capilliposide C (LC-C), an extract from LC Hemsl, has demonstrated multiple anti-cancer effects in several types of cancer. Here, we investigated the potential therapeutic impacts of LC-C on radiosensitivity in lung cancer cells and their underlying mechanisms.Methods: Non-small cell lung cancer cell lines were initially irradiated to generate ionizing radiation (IR)-resistant lung cancer cell lines. RNA-seq analysis was used to examine the whole-transcriptome alteration in IR-resistant lung cancer cells treated with or without LC-C, and the differentially expressed genes with most significance were verified by RT-qPCR. Colony formation assays were performed to determine the effect of LC-C and the target gene ErbB receptor feedback inhibitor 1 (ERRFI1) on radiosensitivity of IR-resistant lung cancer cells. In addition, effects of ERRFI1 on cell cycle distribution, DNA damage repair activity were assessed by flow cytometry and γ-H2AX immunofluorescence staining respectively. Western blotting was performed to identify the activation of related signaling pathways. Tumor xenograft experiments were conducted to observe the effect of LC-C and ERRFI1 on radiosensitivity of IR-resistant lung cancer cells in vivo.Results: Compared with parental cells, IR-resistant lung cancer cells were more resistant to radiation. LC-C significantly enhanced the effect of radiation in IR-resistant lung cancer cells both in vitro and in vivo and validated ERRFI1 as a candidate downstream gene by RNA-seq. Forced expression of ERRFI1 alone could significantly increase the radiosensitivity of IR-resistant lung cancer cells, while silencing of ERRFI1 attenuated the radiosensitizing function of LC-C. Accordingly, LC-C and ERRFI1 effectively inhibited IR-induced DNA damage repair, and ERRFI1 significantly induced G2/M checkpoint arrest. Additional investigations revealed that down-regulation of EGFR/STAT3 pathway played an important role in radiosensitization between ERRFI1 and LC-C. Furthermore, the high expression level of ERRFI1 was associated with high overall survival rates in lung cancer patients.Conclusions: Treatment of LC-C may serve as a promising therapeutic strategy to overcome the radiation resistance and ERRFI1 may be a potential therapeutic target in NSCLC.

Background Radiation-induced cardiac injury results in complex clinical presentations, unique management issues, and increased morbidity and mortality. But the underlying mechanism of radiation-induced cardiac injury is still unclear. The aim of this study is to explain the compositional alterations of innate and adaptive cells after thoracic irradiation and the relationship of macrophage with other adaptive cells. Methods C57BL/6 mice were anesthetized and performed with 20Gy single dose cardiac irradiation. We carried out mice echocardiography to examine cardiac function. Masson and immunohistochemical staining were adopted to analyze cardiac fibrosis. Blood and cardiac tissue were collected 7 days, 4 weeks and 8 weeks after irradiation and sham-irradiated mice were set as a control group. Part of blood and tissue samples were analyzed with mass cytometry. We also used remaining blood samples to measure pro-fibrotic cytokines. Results We observed reduced cardiac diastolic function and pathologically confirmed cardiac fibrosis after thoracic irradiation. Through mass cytometry, we identified that the proportion of neutrophils, macrophages and monocytes elevated. The ratio of T and B cells decreased after irradiation in the blood samples. For tissue samples, the proportion of macrophages, monocytes and neutrophils increased, endothelial cells reduced, but T and B cells also increased. The level of TGF-β, TNF-α, IL-6 climbed considerably, all of them are closely associated with the evolution of macrophage function during recovering phase of cardiac injury. In the correlation plot, we also discovered that CD4+T and CD8+T cells were strongly positively correlated with macrophages. Conclusion We illustrated the immunological response after radiation-induced cardiac fibrosis, and macrophage may play a crucial role during the process. The results might have therapeutic potential for targeting macrophages in order to reduce radiation-induced cardiac fibrosis.

Objective: Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, has shown potential as a candidate radiosensitizer for many types of cancers. This study aimed to explore the radiosensitization mechanism of SAHA in lung cancer cells. Methods: Mutations in p53 were generated by site-directed mutagenesis using polymerase chain reaction. Transfection was performed to generate H1299 cells carrying wild-type or mutant p53. The radiosensitizing enhancement ratio was determined by clonogenic assays. Mitochondrial apoptosis was detected using JC-1 staining and flow cytometry analysis. Results: Our results showed that SAHA induced radiosensitization in H1299 cells expressing wild-type p53, p53^R175H or p53^P223L, but this enhanced clonogenic cell death was not observed in parental H1299 (p53-null) cells or H1299 cells expressing p53 with K120R, A161T and V274R mutations. In SAHA-sensitized cells, mitochondrial apoptosis was induced following exposure to irradiation. Additionally, we observed that a secondary mutation at K120 (K120R) could eliminate p53-mediated radiosensitization and mitochondrial apoptosis. Conclusions: The results of this study suggest that wild-type and specific mutant forms of p53 mediate SAHA-induced radiosensitization by regulating mitochondrial apoptosis, and the stabilization of K120 acetylation by SAHA is the molecular basis contributing to radiosensitization in lung cancer cells.

Background: The development of chemoradiotherapy is urgently needed for locally advanced squamous cell lung cancer due to its poor prognosis and significant toxicity. Carboplatin combined with nab-paclitaxel is a useful choice as first-line therapy in advanced squamous cell lung cancer. This prospective phase II study aimed to explore the efficacy and toxicity of concurrent chemoradiotherapy with nab-paclitaxel, carboplatin, and thoracic radiotherapy in unresectable locally advanced squamous cell lung cancer. Methods: Patients with unresectable stage III squamous cell lung cancer were eligible. All patients received nab-paclitaxel weekly at a dose of 60 mg/m², in combination with carboplatin [area under the plasma concentration time curve (AUC) 2] weekly during concurrent chemoradiotherapy. Thoracic radiation was administered at a dose of 66 Gy/33 fractions. The consolidation chemotherapy consisted of nab-paclitaxel (260 mg/m² on day 1) and carboplatin (AUC 6 on day 1) every 21 days was administered in two cycles after the concurrent chemoradiotherapy. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results: Initially, enrollment of 21 patients was planned; however, the trial was prematurely closed due to slow recruitment. Finally, a total of 8 patients were enrolled between January 2012 and July 2015 from one institute. All patients completed concurrent chemoradiotherapy, and 6 patients (75.0%) received consolidation chemoradiotherapy. The ORR was 75%, with complete response (CR) 1 (12.5%), partial remission 6 (62.5%), stable disease 1 (12.5%), progressive disease 1 (12.5%), respectively. After a median follow-up of 15.2 (range, 2.3–51.5) months, 7 patients were dead, and 1 was alive. The median PFS and OS were 12.1 and 15.2 months, respectively. According to Common Terminology Criteria for Adverse Events version 4.0, 6 patients (75.0%) experienced acute radiation esophagitis, 4 (50.0%) were grade 2 (G2), and 2 (25.0%) were G3; 4 patients (50%) experienced acute radiation pneumonitis, 3 (37.5%) were G2, and 1 (12.5%) was G3. No late radiation-induced esophageal and pulmonary toxicity was observed after 1-year follow-up. Conclusions: Concurrent nab-paclitaxel, carboplatin, and thoracic radiotherapy was shown to be an effective regimen for patients with unresectable locally advanced squamous cell lung cancer; however, further study should exercise caution due to the severe radiation esophagitis.

Background: Few studies to date have assessed the incidence of radiation pneumonitis (RP) in lung cancer patients who have been treated with volumetric modulated arc therapy (VMAT). This study is aimed at reporting the RP incidence rate and the risk factors associated with a symptomatic RP in patients with lung cancer treated with VMAT. Methods: A total of 77 consecutive lung cancer patients treated with VMAT from 2013 through 2015 were reviewed. RP severity was graded according to the Common Terminology Criteria for Adverse Events (CTCEA) v.4. Univariate and multivariate analyses were performed to identify the significant factors associated with RP. Results: VMAT allowed us to achieve most planning objectives on the target volumes and organs at risk, for PTV V_95% =96.8%±3.1%, for lung V₅ =41.3%±8.7%, V₁₀ =30.0%±7.1%, V₂₀ =20.9%±5.7%, for heart V₅ =43.2%±29.9%, for esophagus V₆₀ =8.1%±12.9%. The maximum dose of spinal cord was 34.4±9.5 Gy. The overall incidence of symptomatic RP (grade ≥2 by CTCAE) was 28.6% in the entire cohort, and the rate of grade ≥3 RP was 11.7%. Based on the multivariate analysis, factors predictive of symptomatic RP included lung volume receiving ≥10 Gy (V₁₀) (P=0.019) and C-reactive protein changing level (P=0.013). Conclusions: Our data showed that the incidence rate of RP was acceptable in lung cancer patients treated with VMAT. Additionally, we found that V₁₀ might be an important factor for predicting the development of RP when VMAT was used; but this observation needs to be validated in future studies.

Introduction: Plasma circulating tumor DNA (ctDNA) is an ideal approach to detecting the epidermal growth factor receptor ( EGFR ) T790M mutation, which is a major mechanism of resistance to first‐generation EGFR‐tyrosine kinase inhibitor (TKI) therapy. The present study aimed to explore the association of ctDNA‐identified T790M mutation with disease failure sites and clinical prognosis in non‐small cell lung cancer (NSCLC) patients. Methods: Patients who progressed on first‐generation TKIs were categorized into failure site groups of chest limited (CF), brain limited (BF) and other (OF). Amplification refractory mutation system (ARMS) and droplet digital PCR (ddPCR) were used to identify the T790M mutation in ctDNA. Prognosis was analyzed with Kaplan–Meier methods. Results: Overall concordance between the two methods was 78.3%. According to both ARMS and ddPCR, patients in the OF group had a significantly higher rate of T790M mutation than did patients in the BF and CF groups ( P < 0.001), and a significantly higher T790M mutation rate was also observed in OF‐group patients than in those in the CF and BF groups ( P < 0.001). AZD9291 was found to be an excellent treatment option and yielded the longest survival for T790M+ patients in all groups who had progressed on EGFR‐TKIs; for other treatments, the prognosis of T790M− patient subgroups varied. Conclusions: The present study demonstrates that T790M mutation in ctDNA is associated with failure sites for NSCLC patients after EGFR‐TKI therapy and indicates that both failure site and T790M mutational status greatly influence treatment selection and prognosis.

APS (Acta Pharmacologica Sinica), the top pharmacology research journal based in China, publishes original articles and reviews on all aspects of pharmacology and the related life sciences