Inhibition of OGG1 ameliorates pulmonary fibrosis via preventing M2 macrophage polarization and activating PINK1-mediated mitophagy.

BACKGROUND: 8-Oxoguanine DNA glycosylase (OGG1), a well-known DNA repair enzyme, has been demonstrated to promote lung fibrosis, while the specific regulatory mechanism of OGG1 during pulmonary fibrosis remains unclarified. METHODS: A bleomycin (BLM)-induced mouse pulmonary fibrosis model was established, and TH5487 (the small molecule OGG1 inhibitor) and Mitochondrial division inhibitor 1 (Mdivi-1) were used for administration. Histopathological injury of the lung tissues was assessed. The profibrotic factors and oxidative stress-related factors were examined using the commercial kits. Western blot was used to examine protein expression and immunofluorescence analysis was conducted to assess macrophages polarization and autophagy. The conditional medium from M2 macrophages was harvested and added to HFL-1 cells for culture to simulate the immune microenvironment around fibroblasts during pulmonary fibrosis. Subsequently, the loss- and gain-of function experiments were conducted to further confirm the molecular mechanism of OGG1/PINK1. RESULTS: In BLM-induced pulmonary fibrosis, OGG1 was upregulated while PINK1/Parkin was downregulated. Macrophages were activated and polarized to M2 phenotype. TH5487 administration effectively mitigated pulmonary fibrosis, M2 macrophage polarization, oxidative stress and mitochondrial dysfunction while promoted PINK1/Parkin-mediated mitophagy in lung tissues of BLM-induced mice, which was partly hindered by Mdivi-1. PINK1 overexpression restricted M2 macrophages-induced oxidative stress, mitochondrial dysfunction and mitophagy inactivation in lung fibroblast cells, and OGG1 knockdown could promote PINK1/Parkin expression and alleviate M2 macrophages-induced mitochondrial dysfunction in HFL-1 cells. CONCLUSION: OGG1 inhibition protects against pulmonary fibrosis, which is partly via activating PINK1/Parkin-mediated mitophagy and retarding M2 macrophage polarization, providing a therapeutic target for pulmonary fibrosis.

Nitrogen-doped hydrochars from shrimp waste as visible-light photocatalysts: Roles of nitrogen species.

The increasing shrimp waste production has caused severe environmental problems. In this study, nitrogen-doped hydrochars (NDHCs) were facilely synthesized from shrimp waste and glucose by one-pot hydrothermal carbonization (HTC). The characterizations showed that NDHCs had large surface areas of up to 30.5 m2 g-1 with numerous functional groups on their porous surfaces. The nitrogen content (1.3-2.8%) and species distribution in NDHCs were associated with the amount of added glucose. These NDHCs were applied as visible-light-induced photocatalysts, and their photocatalytic performances were evaluated by methylene blue (MB) degradation. The removal rate of MB reached 88.9% after 1 h of visible light radiation by NDHC-1, which was 2.3 times higher than that of glucose-derived hydrochar (GHC). The mechanism study showed that the improved photoactivity of NDHCs was attributed to the increased adsorption capacity by porous surface and the promoted formation of hydroxyl radicals by synergistic effects of quaternary N and pyrrolic N during photocatalysis. This study offered a green approach to preparing tunable, efficient, and low-cost photocatalyst from waste biomass and insight into the photocatalytic mechanism of hydrochar materials.

Single-cell transcriptomic analysis reveals key immune cell phenotypes in the lungs of patients with asthma exacerbation.

BACKGROUND: Asthma exacerbations are associated with heightened asthma symptoms, which can result in hospitalization in severe cases. However, the molecular immunologic processes that determine the course of an exacerbation remain poorly understood, impeding the progression of development of effective therapies. OBJECTIVE: Our aim was to identify candidate genes that are strongly associated with asthma exacerbation at a cellular level. METHODS: Subjects with asthma exacerbation and healthy control subjects were recruited, and bronchoalveolar lavage fluid was isolated from these subjects via bronchoscopy. Cells were isolated through fluorescence-activated cell sorting, and single-cell RNA sequencing was performed on enriched cell populations. RESULTS: We showed that the levels of monocytes, CD8+ T cells, and macrophages are significantly elevated in the bronchoalveolar lavage fluid of patients. A set of cytokines and intracellular transduction regulators are associated with asthma exacerbations and are shared across multiple cell clusters, forming a complicated molecular framework. An additional group of core exacerbation-associated modules is activated, including eukaryotic initiation factor 2 signaling, ephrin receptor signaling, and C-X-C chemokine receptor type 4 signaling in the subpopulations of CD8+ T cells (C1-a) and monocyte clusters (C7 clusters), which are associated with infection. CONCLUSION: Our study identified a significant number of severe asthma-associated genes that are differentially expressed by multiple cell clusters.

Label-free and sensitive MiRNA detection based on turn-on fluorescence of DNA-templated silver nanoclusters coupled with duplex-specific nuclease-assisted signal amplification.

A novel strategy for microRNAs (miRNAs) detection has been developed utilizing duplex-specific nuclease-assisted signal amplification (DSNSA) and guanine-rich DNA-enhanced fluorescence of DNA-templated silver nanoclusters (AgNCs). The combination between target miRNA, DSNSA, and AgNCs is achieved by the unique design of DNA sequences. Target miRNA opens the hairpin structure of the Hairpin DNA probe (HP) by hybridizing with the HP and initiates the duplex-specific nuclease-assisted signal amplification (DSNSA) reaction. The DSNSA reaction generates the release of the guanine-rich DNA sequence, which can turn on the fluorescence of the dark AgNCs by hybridizing with the DNA template of the dark AgNCs. The fluorescence intensity of AgNCs corresponds to the dosage of the target miRNA. This is measured at 630 nm by exciting at 560 nm. The constructed method exhibits a low detection limit (~8.3 fmol), a great dynamic range of more than three orders of magnitude, and excellent selectivity. Moreover, it has a good performance for miR-21 detection in complex biological samples. A novel strategy for microRNAs (miRNAs) detection has been developed utilizing duplex-specific nuclease-assisted signal amplification (DSNSA) and guanine-rich DNA-enhanced fluorescence of DNA-templated silver nanoclusters (AgNCs).

Efficacy and Safety of Omalizumab for Chronic Spontaneous Urticaria: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Omalizumab has been proposed as a possible effective treatment of chronic spontaneous urticaria (CSU). STUDY QUESTION: We aimed to access the efficacy and safety of omalizumab in the treatment of CSU based on qualified, randomized controlled trials (RCTs). DATA SOURCES: PubMed, the Cochrane library, and Embase databases. STUDY DESIGN: Computerized search by index words was performed to identify qualified RCTs, and relevant literature sources were also searched. RESULT: Nine RCTs were included in the meta-analysis with 1612 patients in the omalizumab group and 1251 patients in the placebo group. Compared with the placebo group, omalizumab significantly decreased the weekly itch score after therapy [Weighted Mean Difference (WMD), -3.94; 95% confidence interval (CI), -4.64 to -3.24], the weekly hive score (WMD, -5.27; 95% CI, -6.17 to -4.38), the dermatology life quality index (DLQI; WMD, -3.58; 95% CI, -4.66 to -2.50), and the urticaria activity score over 7 days (UAS7; WMD, -9.51; 95% CI, -10.94 to -8.08). There was no significant difference in the incidence of adverse events (AE) [relative risk (RR), 1.01; 95% CI, 0.91-1.12], serious AE (RR, 0.85; 95% CI, 0.57-1.27), and severe AE (RR, 0.83; 95% CI, 0.60-1.14) between the 2 groups. Compared with the placebo, omalizumab significantly decreased the weekly itch score and weekly hive score after therapy in patients receiving 75, 150, and 300 mg omalizumab, respectively. DLQI was significantly reduced in patients receiving 150 and 300 mg of omalizumab, respectively. In all the subgroup of UAS7, omalizumab significantly decreased the score compared with the placebo. Only patients receiving 600-mg omalizumab had a significantly higher AE incidence versus placebo. There was no significant difference in serious and severe AE between the 2 groups. CONCLUSION: Omalizumab caused a significantly greater reduction in weekly itch score, weekly hive score, DLQI, and UAS7 in CSU patients than the placebo. However, high-quality, multicenter RCTs with a larger sample size are needed to confirm the safety of omalizumab, and whether AEs are caused by omalizumab or other factors.

[Treatment of Guishen Zhiyang Recipe for Senile Pruritus Patients with Blood Deficiency and Hy- peractivity of Gan-yang Syndrome].

Objective To observe the clinical efficacy of Guishen Zhiyang Recipe (GZR) in trea- ting senile pruritus patients with blood deficiency and hyperactivity of Gan-yang syndrome (BDHGYS) and to study the mechanism in nervous-endocrine-immune systems. Methods Ninety senile pruritus pa- tients were assigned to the treatment group and the control group by complete randomized lot, 45 in each group. Totally 41 patients in the treatment group and 38 patients in the control group completed the trial. Patients in the treatment group took GZR, while those in the control group took Fuyang Granule (FG). Ex- ternal application of Binghuang Fule Soft Ointment was performed to all patients. The therapeutic course for all was 8 weeks. Symptoms and efficacy changes in skin lesion were observed in the two groups. Lev- els of stem cell factor (SCF) , dynorphin (DYN) , testosterone (T) , estradiol (E2) , and IL-4 were detec- ted in the two groups using double antibody sandwich ELISA. Results Compared with before treatment, pruritus degree, scratching area, scaling, lichenoid lesion, irritability and restlessness, dysphoria, dry pharynx, dizziness, and tinnitus all decreased in the two groups after 8 weeks of treatment (P <0. 05). Scores of Chinese medical syndromes all decreased after 4 and 8 weeks of treatment (P <0. 05). Levels of SCF and DYN obviously decreased in the two groups after 4 and 8 weeks of treatment (P <0. 05,P < 0. 01). Compared with the control group, obvious improvement was seen in pruritus degree, scratching number, scaling, irritability and restlessness , dysphoria, dizziness , and tinnitus(P <0. 05) ; total scores of Chinese medical syndromes decreased (P <0. 05) ; SCF also decreased (P <0. 05) in the treatment group after 8 weeks of treatment. Conclusions Based on external application of Binghuang Fule Soft Ointment, GZR showed better efficacy than that of the control. It had certain roles in regulating related mediator levels that might affect nervous-endocrine-immune systems.

Precision patient selection for improved detection of circulating genetically abnormal cells in pulmonary nodules.

Circulating genetically abnormal cells (CACs) have emerged as a promising biomarker for the early diagnosis of lung cancer, particularly in patients with pulmonary nodules. However, their performance may be suboptimal in certain patient populations. This study aimed to refine patient selection to improve the detection of CACs in pulmonary nodules. A retrospective analysis was conducted on 241 patients with pulmonary nodules who had undergone pathological diagnosis through surgical tissue specimens. Utilizing consensus clustering analysis, the patients were categorized into three distinct clusters. Cluster 1 was characterized by older age, larger nodule size, and a higher prevalence of hypertension and diabetes. Notably, the diagnostic efficacy of CACs in Cluster 1 surpassed that of the overall patient population (AUC: 0.855 vs. 0.689, P = 0.044). Moreover, for Cluster 1, an integrated diagnostic model was developed, incorporating CACs, sex, maximum nodule type, and maximum nodule size, resulting in a further improved AUC of 0.925 (95% CI 0.846-1.000). In conclusion, our study demonstrates that CACs detection shows better diagnostic performance in aiding the differentiation between benign and malignant nodules in older patients with larger pulmonary nodules and comorbidities such as diabetes and hypertension. Further research and validation are needed to explore how to better integrate CACs detection into clinical practice.

An ultrasensitive terminal protection-based real-time fluorescence approach for protein detection via an isothermal exponential amplification reaction.

In this assay, based on the terminal protection of small-molecule-linked DNA, a new ultrasensitive real-time fluorescence strategy combined with an isothermal exponential amplification reaction (IEXPAR) has been established for protein assay. By the clever design of DNA, terminal protection is combined with efficient IEXPAR. The target protein explicitly binds to small molecules attached to the template DNA, protecting the template DNA from exonuclease I (Exo I) degradation. The added DNA primer hybridizes with the protected template DNA and triggers the following IEXPAR. IEXPAR has a super amplification efficiency of 106-109 times. The IEXPAR yields numerous double-stranded DNA (dsDNA) molecules. The fluorescence dye SYBR Green I (SG), which is sensitive to dsDNA, is used to determine the real-time fluorescence of the IEXPAR. Conversely, without the target protein, the template DNA is hydrolyzed by Exo I, failing to trigger the IEXPAR. The intriguing combination of IEXPAR and terminal protection realizes the ultrasensitive detection of protein. As low as 100 fmol L-1 SA and 200 pg mL-1 folic acid (FR) are accurately detected.

Pharmacokinetics/pharmacodynamics of ivosidenib in advanced IDH1-mutant cholangiocarcinoma: findings from the phase III ClarIDHy study.

PURPOSE: Report pharmacokinetic (PK)/pharmacodynamic (PD) findings from the phase III ClarIDHy study and any association between PK/PD parameters and treatment outcomes in this population. METHODS: Patients with mutant isocitrate dehydrogenase 1 (mIDH1) advanced cholangiocarcinoma were randomized at a 2:1 ratio to receive ivosidenib or matched placebo. Crossover from placebo to ivosidenib was permitted at radiographic disease progression. Blood samples for PK/PD analyses, a secondary endpoint, were collected pre-dose and up to 4 h post-dose on day (D) 1 of cycles (C) 1 - 2, pre-dose and 2 h post-dose on D15 of C1 - 2, and pre-dose on D1 from C3 onwards. Plasma ivosidenib and D-2-hydroxyglutarate (2-HG) were measured using liquid chromatography-tandem mass spectrometry. All clinical responses were centrally reviewed previously. RESULTS: PK/PD analysis was available for samples from 156 ivosidenib-treated patients. Ivosidenib was absorbed rapidly following single and multiple oral doses (time of maximum observed plasma concentration [Tmax] of 2.63 and 2.07 h, respectively). Ivosidenib exposure was higher at C2D1 than after a single dose, with low accumulation. In ivosidenib-treated patients, mean plasma 2-HG concentration was reduced from 1108 ng/mL at baseline to 97.7 ng/mL at C2D1, close to levels previously observed in healthy individuals. An average 2-HG inhibition of 75.0% was observed at steady state. No plasma 2-HG decreases were seen with placebo. Plasma 2-HG reductions were observed in ivosidenib-treated patients irrespective of best overall response (progressive disease, or partial response and stable disease). CONCLUSION: Once-daily ivosidenib 500 mg has a favorable PK/PD profile, attesting the 2-HG reduction mechanism of action and, thus, positive outcomes in treated patients with advanced mIDH1 cholangiocarcinoma. CLINICAL TRIAL REGISTRATION: NCT02989857 Registered February 20, 2017.

Association of dietary iron intake with diabetic kidney disease among individuals with diabetes.

PURPOSE: The current study investigated the correlation between dietary iron intake and diabetic kidney disease among diabetic adults. METHODS: This cross-sectional study enrolled 8118 participants who suffered from diabetes from the National Health and Nutrition Examination Survey (NHANES) 1999-2018. Dietary iron intake was obtained from 24 h recall interviews, and diabetic kidney disease was defined as eGFR < 60 mL/min per 1.73 m2 or albumin creatinine ratio (ACR) ≥ 30 mg/g. Three weighted logistic regression models were utilized to investigate odd ratio (OR) and 95% CIs for diabetic kidney disease. Stratified analyses were performed by gender, age, BMI, HbA1c, hypertension status, and smoking status, and diabetes types. RESULTS: Among 8118 participants (51.6% male, mean age 61.3 years), 40.7% of participants suffered from diabetic kidney disease. With the adjustment of potential covariates, we found that ≥ 12.59 mg of dietary iron was related to a lower risk of diabetic kidney disease (OR = 0.78, 95% CI: 0.63 to 0.96; OR = 0.79, 95% CI: 0.63 to 0.98). In stratified analyses, higher iron intake was negatively related to diabetic kidney disease, especially among those who were male, < 60 years, those with hypertension, those with HbA1c < 7.0%, and those who were ex-smokers. The result remained robust in sensitivity analyses. CONCLUSION: We found that ≥ 12.59 mg of dietary iron is associated with a lower risk of diabetic kidney disease, especially in those who were male, younger, heavier weight, have better blood sugar control, and those who were ex-smokers.

Corrigendum: Clinical characteristics and prognosis of patients with pulmonary mucoepidermoid carcinoma: a SEER-based analysis.

[This corrects the article DOI: 10.3389/fonc.2021.601185.].

Association between dietary protein intake and mortality among patients with diabetic kidney disease.

AIMS: This study aimed to investigate the association between dietary protein intake and mortality among patients with diabetic kidney disease. METHODS: The research encompassed a total of 2901 participants diagnosed with diabetic kidney disease, drawn from the National Health and Nutrition Examination Survey (NHANES). To determine outcomes related to all-cause and cardiovascular mortality, connections were established with the National Death Index up until December 31, 2019. Estimations of hazard ratios (HRs) and their corresponding 95 % confidence intervals (CIs) were conducted using Cox proportional hazard ratio models. RESULTS: During the 261,239 person-years of follow-up, 1236 deaths were recorded. After multivariate adjustment, the weighted hazard ratio (HR) and 95 % CIs for participants with 1.0-1.2 g/kg of protein intake was 0.65 (0.44, 0.96) for all-cause mortality. A higher proportion of animal protein intake was found to be associated with an increased mortality risk. Stratified analyses showed that higher protein intake benefited older participants. CONCLUSIONS: In diabetic kidney disease patients, 1.0-1.2 g/kg of protein was associated with lower mortality and 0.6-1.2 g/kg of protein especially benefitted patients ≥60 years.

Maculopapular Drug Eruption Caused by Finasteride: A Case Report.

A 76-year-old male developed a maculopapular rash on his trunk and extremities. The rash appeared 2 months after Finasteride administration for his prostatic hyperplasia. Clinical suspicion was of drug exanthema due to Finasteride. The clinical and histologic data were compatible with pharmacologic eruption by Finasteride.

"Entrepreneurship" from the lens of enlightenment: Impacts of religiosity and spiritual intelligence on social entrepreneurial intentions.

Despite an escalated gravity of interest in exploring factors that shape university students' social entrepreneurial intentions, there are significant gaps in our understanding of this phenomenon. The current study examines the boundary effects of religiosity and spiritual intelligence to predict university students' social entrepreneurial intentions. The authors collected the data from university students in their final years in multiple waves and employed SmartPLS (v 4.0) for data analysis. Our findings indicate that religiosity can affect social entrepreneurial intentions through two paths: intrinsic motivation mediates the association between intrinsic religiosity and social entrepreneurial intentions, and extrinsic motivation mediates the relationship between extrinsic religiosity and social entrepreneurial intentions. Further, spiritual intelligence moderates the relationship between intrinsic religiosity and social entrepreneurial intentions, mediated by intrinsic motivation such that at high levels of spiritual intelligence the association is more potent and vice versa. This is the first study that examines the boundary conditions of social entrepreneurial intentions of university students by employing the lens of religiosity and spirituality. The paper presents substantial theoretical and practical implications.

Pleural cryptococcosis diagnosed by pleural biopsy in an immunocompromised patient: a case report.

Objective: The aim of this study is to report an isolated pleural cryptococcosis with pleural effusion as the only manifestation, confirmed by pleural biopsy in a patient with thymoma combined with myasthenia gravis, who developed pleural effusion of unknown origin after long-term glucocorticoids and tacrolimus therapy. Methods: Pathological examination of the right pleural biopsy tissue from a patient with unexplained recurrent pleural effusion was implemented. Morphological analysis of the fungal component and metagenomic next-generation sequencing (mNGS) on the pleural tissue were performed. Results: A biopsy specimen of the right pleura revealed numerous yeast-like organisms surrounded by mucous capsules and Cryptococcus neoformans was detected by mNGS with a species-specific read number (SSRN) of 4, confirming the diagnosis of pleural cryptococcosis. Pleural effusion was eliminated with amphotericin B and fluconazole, and healthy status was maintained at the time of review 1 year later. Conclusion: Cryptococcosis, manifested by simple pleural effusion, is extremely rare, but when repeated pleural effusion occurs in immunocompromised patients or in patients with malignant tumors, the possibility of cryptococcosis should be treated with high vigilance and pleural biopsy is recommended if necessary in order to confirm the diagnosis.

Transcriptomic profiling and longitudinal study reveal the relationship of anti-MDA5 titer and type I IFN signature in MDA5+ dermatomyositis.

Objective: This study aimed to investigate the relationship between anti-MDA5 titer and type I IFN signature in patients with MDA5+ DM. Methods: We explored the transcriptome profiling of PBMCs in MDA5+ DM patients with high-titer of antibody at disease onset or relapse and normal low-titer after treatment and healthy donors. Subsequently, we revealed the dynamic relationship between serum type I IFN scores and antibody titers. Result: Differentially expressed genes in MDA5+ DM patients were enriched for related pathways and biological functions linked to viruses and cytokines compared to healthy donors. Similar differences remained pooled between the high-titer and low-titer group, and type I-specific interferon response genes showed upregulation in high-titer group. Significant correlations were found between anti-MDA5 titers and type I IFN scores (r = 0.50, P< 0.001). Contemporaneous anti-MDA5 titers revealed to be significantly higher in the group with ultra-high type I IFN scores (vs. high group, P = 0.027; vs. low group, P< 0.001). Longitudinal assessment of type I IFN scores and anti-MDA5 titers, including pre- and post-treatment changes at initial diagnosis and dynamic changes during treatment, presented an asynchrony between the two parameters in response to treatment. Conclusion: Anti-MDA5 antibody titers correlated with type I IFN signature in patients with MDA5+ DM and they both changed dynamically but not synchronously over the course of treatment.

Diagnostic efficacy of metagenomic next generation sequencing in bronchoalveolar lavage fluid for proven invasive pulmonary aspergillosis.

Objective: To assess the diagnostic efficacy of metagenomic next generation sequencing (mNGS) for proven invasive pulmonary aspergillosis (IPA). Methods: A total of 190 patients including 53 patients who had been diagnosed with proven IPA were retrospectively analyzed. Using the pathological results of tissue biopsy specimens as gold standard, we ploted the receiver operating characteristic (ROC) curve to determine the optimal cut-off value of mNGS species-specific read number (SSRN) of Aspergillus in bronchoalveolar lavage fluid (BALF)for IPA. Furthermore, we evaluated optimal cut-off value of mNGS SSRN in different populations. Results: The optimal cut-off value of Aspergillus mNGS SSRN in BALF for IPA diagnosis was 2.5 for the whole suspected IPA population, and 1 and 4.5 for immunocompromised and diabetic patients, respectively. The accuracy of mNGS was 80.5%, 73.7% and 85.3% for the whole population, immunocompromised and diabetic patients, respectively. Conclusions: The mNGS in BALF has a high diagnostic efficacy for proven IPA, superioring to Aspergillus culture in sputum and BALF and GM test in blood and BALF. However, the cut-off value of SSRN should be adjusted when in different population.

Long non-coding RNA DSCAS regulates cisplatin sensitivity in lung squamous cell carcinoma by competitively binding to miR-646-3p.

Background: Platinum-based chemotherapy is the main treatment for advanced lung squamous cell carcinoma (LUSC). Eventually, patients with LUSC develop resistance to cisplatin, which affects the prognosis. Hence, the researchers sought to find a lncRNA in LUSC that affects resistance to cisplatin. Methods: The lncRNA microarray assay was used to screen the differential expression of lncRNA. qPCR was used to detect lncRNA DSCAS (DSCAS) expression in tissues and cell lines. Lentiviral transfection was used to regulate the expression of DSCAS. CCK-8, colony formation, wound healing, transwell, and flow cytometry assays were used to assess the biological behaviors and sensitivity to cisplatin of LUSC cell. RNA-RNA interaction was tested using the dual luciferase reporting assay, RNA-IP, and RNA-RNA pull-down assay. The downstream pathway of DSCAS was verified by qPCR and Western blotting assays. Results: DSCAS was highly expressed in LUSC tissues and cells, and its expression levels were higher in cisplatin-insensitive tissues than in cisplatin-sensitive tissues. Elevation of DSCAS promoted cell proliferation, migration and invasion as well as increased cisplatin resistance of lung cancer cells, while demotion of DSCAS inhibited cell proliferation, migration and invasion as well as decreased the cisplatin resistance of lung cancer cells. DSCAS bound to miR-646-3p to regulate the expression of Bcl-2 and Survivin, which affected the cell apoptosis and sensitivity to cisplatin in LUSC cells. Conclusions: DSCAS regulates biological behavior and cisplatin sensitivity in LUSC cells by competitively binding to miR-646-3p to mediate the expression of Survivin and Bcl-2, known as apoptosis-related proteins.

[Evaluation of Efficacy and Prognosis Analysis of Stage III-IV SMARCA4-deficient 
Non-small Cell Lung Cancer Treated by PD-1 Immune Checkpoint Inhibitors plus 
Chemotherapy and Chemotherapy].

BACKGROUND: The SMARCA4 mutation has been shown to account for at least 10% of non-small cell lung cancer (NSCLC). In the present, conventional radiotherapy and targeted therapy are difficult to improve outcomes due to the highly aggressive and refractory nature of SMARCA4-deficient NSCLC (SMARCA4-DNSCLC) and the absence of sensitive site mutations for targeted drug therapy, and chemotherapy combined with or without immunotherapy is the main treatment. Effective SMARCA4-DNSCLC therapeutic options, however, are still debatable. Our study aimed to investigate the efficacy and prognosis of programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICIs) in combination with chemotherapy and chemotherapy in patients with stage III-IV SMARCA4-DNSCLC. METHODS: 46 patients with stage III-IV SMARCA4-DNSCLC were divided into two groups based on their treatment regimen: the chemotherapy group and the PD-1 ICIs plus chemotherapy group, and their clinical data were retrospectively analyzed. Efficacy assessment and survival analysis were performed in both groups, and the influencing factors for prognosis were explored for patients with SMARCA4-DNSCLC. RESULTS: Male smokers are more likely to develop SMARCA4-DNSCLC. There was no significant difference in the objective response rate (76.5% vs 69.0%, P=0.836) between chemotherapy and the PD-1 ICIs plus chemotherapy or the disease control rate (100.0% vs 89.7%, P=0.286). The one-year overall survival rate in the group with PD-1 ICIs plus chemotherapy was 62.7%, and that of the chemotherapy group was 46.0%. The difference in median progression-free survival (PFS) between the PD-1 ICIs plus chemotherapy group and the chemotherapy group was statistically significant (9.3 mon vs 6.1 mon, P=0.048). The results of Cox regression analysis showed that treatment regimen and smoking history were independent influencing factors of PFS in patients with stage III-IV SMARCA4-DNSCLC, and family history was an individual influencing factor of overall survival in patients with stage III-IV SMARCA4-DNSCLC. CONCLUSIONS: Treatment regimen may be a prognostic factor for patients with SMARCA4-DNSCLC, and patients with PD-1 ICIs plus chemotherapy may have a better prognosis.