Objective
KRAS mutation plays a critical role in the initiation and development of non‐small cell lung cancer (NSCLC). KRAS‐mutant patients exhibit diverse response to chemotherapy. KRAS co‐mutation ...subtypes and their prognosis value in advanced Chinese NSCLC patients remain largely elusive.
Methods
A total of 1126 Chinese advanced NSCLC patients from Xiangya hospital were screened by capture‐based ultra‐deep sequencing for KRAS mutation between January 2015 and December 2016. Survival analyses were performed using Kaplan‐Meier analysis.
Results
Among the patients screened, 84 cases were detected with KRAS mutation (7.5%). All of them were non‐squamous NSCLC and received pemetrexed plus platinum as the first‐line treatment. The most frequent KRAS co‐mutation genes were TP53 (29%), TP53/LKB1 (19%), and LKB1 (14%). Our data revealed that patients with KRAS co‐mutation had poorer prognosis in comparison with those harboring single KRAS mutation. Furthermore, patients with KPL (KRAS mutated with TP53 and LKB1) subtype, which was a novel subtype, had the shortest progression‐free survival (PFS) in all types of KRAS co‐mutation patients (P < .0001). The PFS and overall survival (OS) of patients with KRASG12D mutation were inferior than those with KRASG12C mutation or KRASG12V mutation. Patients in KRASG>T type had significantly longer survival than those in KRASG>C type or KRASG>A type.
Conclusion
Our study revealed that concurrent genomic alterations can further stratify KRAS‐mutant lung adenocarcinoma patients into various subgroups with distinctive therapeutic responses and differential survival outcomes. The KPL is a novel and less responsive subtype among KRAS‐mutated NSCLC, and further investigation of effective treatment for this subtype is warranted.
Our study revealed that concurrent genomic alterations can further stratify KRAS‐mutant lung adenocarcinoma patients into various subgroups with distinctive therapeutic responses and differential survival outcomes. The KPL is a novel and less responsive subtype among KRAS‐mutated NSCLC, and further investigation of effective treatment for this subtype is warranted.
Background:
The recommended delivery mode for bronchodilators in bronchodilator responsiveness (BDR) testing remains controversial.
Objective:
To compare the efficacy of salbutamol administration ...using a nebulizer versus a metered-dose inhaler (MDI) with spacer in BDR testing.
Design:
A retrospective study.
Methods:
This study examined the data of patients with chronic obstructive pulmonary disease who completed BDR testing between 1 December 2021 and 30 June 2022, at Xiangya Hospital, Central South University. After administering 400 μg of salbutamol through an MDI with spacer or 2.5 mg using a nebulizer, the changes in forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were analyzed in patients with moderate-to-very severe spirometric abnormalities pre-bronchodilator FEV1 percentage predicted values (FEV1%pred) ⩽59%. Significant responsiveness was assessed as >12% and >200 mL improvement in FEV1 and/or FVC or >10% increase in FEV1%pred or FVC percentage predicted values (FVC%pred) from pre- to post-bronchodilator administration.
Results:
Of the enrolled 894 patients, 83.2% were male (median age, 63 years). After propensity score matching, 240 pairs of patients were selected. The increment in FEV1 and increased FEV1 relative to the predicted value (ΔFEV1%pred) were significantly higher in patients <65 years and those with severe spirometric abnormalities in the nebulization group than patients in the MDI group (all p < 0.05). Compared with MDI with spacer, patients who used nebulization had a 30 mL greater increase in ΔFEV1 (95% CI: 0.01–0.05, p = 0.004) and a 1.09% greater increase in ΔFEV1%pred (95% CI: 0.303–1.896, p = 0.007) from baseline. According to the > 12% and >200 mL increase criterion, the significant BDR rate with nebulization was 1.67 times higher than that with an MDI with spacer (OR = 1.67, 95% CI: 1.13–2.47, p = 0.009).
Conclusion:
Salbutamol delivered using a nebulizer may be preferable to an MDI with spacer in certain circumstances. Nebulization has the potential to increase responsiveness to salbutamol in BDR testing.
Plain language summary
Nebulization versus metered-dose inhaler and spacer in bronchodilator responsiveness testing
Bronchodilator responsiveness testing is commonly undertaken as an important part of spirometry testing to determine the degree of volume and airflow improvement after bronchodilator administration. BDR testing results may affect patients’ diagnosis and treatment. This study compared the effects of two delivery models (a metered dose inhaler (MDI) with spacer and nebulization) on responsiveness to bronchodilators and the results of bronchodilator responsiveness testing among patients with chronic obstructive pulmonary disease. We found that the increment in forced expiratory volume in one second were significantly higher in patients aged <65 years and in those with severe spirometric abnormalities in the nebulization group than in those in the MDI group. The study provides evidence that salbutamol delivered by a nebulizer is preferable to an MDI with spacer in patients <65 years and in those with severe spirometric abnormalities and could increase positive responsiveness to bronchodilators. The study will assist in clinical decision-making by selecting the appropriate dosing regimen for different patients.
Massive hemoptysis is one of emergency and critical diseases of the respiratory system. The definition of massive hemoptysis has always been different in the literature, which often depends on the ...quantitative estimation of the amount of hemoptysis, such as the amount of hemoptysis being in the range of 300-600 mL within 24 h, or hemoptysis more than 3 times within 1 week. Each amount of hemoptysis that is greater than 100 mL can be considered as massive hemoptysis, but the amount of hemoptysis is difficult to accurately estimate. Therefore, massive hemoptysis can be defined as any life-threatening hemoptysis and any hemoptysis that may cause airway obstruction and asphyxia. Massive hemoptysis accounts for approximately 5% of all hemoptysis cases and usually indicates the presence of a potentially severe respiratory or systemic disease. The mortality rate of massive hemoptysis is about 6.5-38%. The cause of death is generally shock caused by airway obstruction or excessive bleeding, and asphyxia is the main cause of death. At present, due to insufficient understanding of massive hemoptysis, there are limited technical means in the etiological diagnosis and untimely or improper treatment, resulting in high mortality of massive hemoptysis. Therefore, the diagnosis and treatment of massive hemoptysis needs to be standardized.
Profilin 1 (PFN1), an actin-binding protein, plays contrasting roles in the metastasis of several cancers; however, its role in non-small cell lung cancer (NSCLC) metastasis remains unclear. Here, ...PFN1 expression was upregulated in metastatic NSCLC tissues. PFN1 overexpression significantly promotes NSCLC metastasis
and
. Proteomics analysis revealed PFN1 involvment in microvesicles (MVs) secretion.
experiments confirmed that PFN1 overexpression increased secretion of MVs. MVs are important mediators of metastasis. Here, we show an increased abundance of MVs in the sera of patients with metastatic NSCLC compared to that in the sera of patients with non-metastatic NSCLC. Both
and
experiments revealed that PFN1 could increase MV secretion, and MVs derived from PFN1-overexpressing cells markedly promoted NSCLC metastasis. We then elucidated the mechanisms underlying PFN1-mediated regulation of MVs and found that PFN1 could interact with ROCK1 and enhance its kinase activity to promote myosin light chain (MLC) phosphorylation for MV secretion. Inhibition of ROCK1 decreased MV secretion and partially reversed the PFN1-induced promotion of NSCLC metastasis. Collectively, these findings show that PFN1 regulates MV secretion to promote NSCLC metastasis. PFN1 and MVs represent potential predictors or therapeutic targets for NSCLC metastasis.
Asthma is characterized as a chronic inflammatory airway disease. Iron accumulation is related to asthma pathogenesis. Transferrin receptor 1(TFR1) expression is associated with intracellular iron ...overload in macrophages. In our study, we explored the association among TFR1 expression, the inflammatory macrophage phenotype, and asthma severity.
Induced sputum was collected from 50 asthma patients. Real-time PCR was used to evaluate mRNA expression. The status of inflammatory macrophage phenotype was assessed using flow cytometry.
TFR1 levels were inversely correlated with forced expiratory volume in 1 s (FEV
)/forced vital capacity (FVC) and FEV
/vital capacity (VC). Among inflammatory cytokines, TFR1 expression was positively correlated with IL-1β, TNF-α, IL-6, IFN-γ, and IL-17A mRNA expression in induced sputum. Moreover, TFR1 expression was positively correlated with the number of proinflammatory M1 macrophages and iNOS expression in induced sputum. Neutrophil counts in induced sputum were significantly and positively related to TFR1 expression. Furthermore, TFR1 expression showed an increasing trend in asthma patients with no family history. Our findings indicated that TFR1 expression was consistent with the asthma severity index, especially the proinflammatory M1 macrophage phenotype. TFR1 expression may be a good marker to indicate asthma severity.
proto-oncogene amplification (amp) is an important mechanism underlying acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, the optimal ...treatment strategy after acquiring
amp-mediated EGFR-TKI resistance remains controversial. Our study compared three treatment strategies for patients with
-mutant non-small-cell lung cancer (NSCLC) who were detected with
amp at EGFR-TKI progression using next-generation sequencing.
Of the 70 patients included in the study, 38 received EGFR-TKI + crizotinib, 10 received crizotinib monotherapy, and 22 received chemotherapy. Clinical outcomes and molecular profiles were analyzed.
The objective response rate was 48.6% for EGFR-TKI + crizotinib group, 40.0% for crizotinib monotherapy group, and 18.2% for chemotherapy group. Patients who received EGFR-TKI + crizotinib had significantly longer progression-free survival than those who received crizotinib or chemotherapy (5.0
. 2.3
. 2.9 months, p = 0.010), but overall survival was comparable (10.0
. 4.1
. 8.5 months, p = 0.088).
mutation (58.5%) and
amp (42.9%) were frequent concurrent mutations of the cohort. Progression-free survival was significantly longer for patients with either concurrent
mutation (n = 17) (6.0
. 2.3
. 2.9 months, p = 0.009) or
amp (n = 13) (5.0
. 1.2
. 2.4 months, p = 0.016) in the EGFR-TKI + crizotinib group than the other two regimen. Potential acquired resistance mechanisms to EGFR-TKI + crizotinib included
-T790M (n = 2),
L718Q (n = 1),
-S645C (n = 1),
-D1228H (n = 1),
-V600E (n = 1),
-Q61H (n = 1),
amp (n = 1),
amp (n = 1),
amp (n = 1), and
amp (n = 1).
Our study provides real-world clinical evidence from a large cohort that simultaneous inhibition of
and
could be a more effective therapeutic strategy for patients with
amp acquired from EGFR-TKI therapy.
Objective
Lung involvement is a major cause of morbidity and mortality in patients with rheumatic diseases. This study aimed to assess the application value of metagenomic next-generation sequencing ...(mNGS) for identifying pathogens in patients with rheumatic diseases and diffuse pulmonary lesions.
Methods
This retrospective study included patients who were diagnosed with rheumatic diseases and presenting diffuse pulmonary lesions on chest radiography in Xiangya Hospital from July 2018 to May 2022. Clinical characteristics were summarized, including demographics, symptoms, comorbidities, radiological and laboratory findings, and clinical outcomes. Pulmonary infection features of these patients were analyzed. Furthermore, diagnostic performance of mNGS and conventional methods (including smear microscopy, culture, polymerase chain reaction assay, and serum immunological test) in identifying pulmonary infections and causative pathogens were compared.
Results
A total of 98 patients were included, with a median age of 58.0 years old and a female proportion of 59.2%. Of these patients, 71.4% showed the evidence of pulmonary infections. Combining the results of mNGS and conventional methods, 129 infection events were detected, including 45 bacterial, 40 fungal and 44 viral infection events. Pulmonary mixed infections were observed in 38.8% of patients. The detection rates of mNGS for any pathogen (71.4% vs 40.8%,
P
< 0.001) and mixed pathogens (40.8% vs 12.2%,
P
< 0.001) were higher than that of conventional methods. Moreover, mNGS had a significantly higher sensitivity (97.1% vs. 57.1%,
P
< 0.001) than conventional methods in identifying pulmonary infections, while its specificity (92.9% vs. 96.4%,
P
= 0.553) were comparable to conventional methods. Antimicrobial and antirheumatic treatments were markedly modified based on mNGS results in patients with rheumatic diseases and diffuse pulmonary lesions.
Conclusions
For patients diagnosed with rheumatic diseases and presenting diffuse pulmonary lesions, mNGS is a powerful complement to conventional methods in pathogen identification due to its high efficiency and broad spectrum. Early application of mNGS can provide guidance for precision treatment, and may reduce mortality and avoid antibiotic abuse.
Chronic obstructive pulmonary disease (COPD) is a chronic lung inflammatory disease which has a close relationship with aging. Genome-wide analysis reveals that DNA methylation markers vary obviously ...with age. DNA methylation variations in peripheral blood have the potential to be biomarkers for COPD. However, the specific DNA methylation of aging-related genes in the peripheral blood of COPD patients remains largely unknown.
Firstly, 9 aging-related differentially expressed genes (DEGs) in COPD patients were screened out from the 25 aging-related genes profile through a comprehensive screening strategy. Secondly, qPCR and multiple targeted bisulfite enrichment sequencing (MethTarget) were used to detect the mRNA level and DNA methylation level of the 9 differentially expressed genes in the peripheral blood of 60 control subjects and 45 COPD patients. The candidate functional CpG sites were selected on the basis of the regulation ability of the target gene expression. Thirdly, the correlation was evaluated between the DNA methylation level of the key CpG sites and the clinical parameters of COPD patients, including forced expiratory volume in one second (FEV1), forced expiratory volume in one second as percentage of predicted volume (FEV1%), forced expiratory volume/ forced vital capacity (FEV/FVC), modified British medical research council (mMRC) score, acute exacerbation frequency and the situation of frequent of acute aggravation (CAT) score. Lastly, differentially methylated CpG sites unrelated to smoking were also determined in COPD patients.
Of the 9 differentially expressed aging-related genes, the mRNA expression of 8 genes were detected to be significantly down-regulated in COPD group, compared with control group. Meanwhile, the methylated level of all aging-related genes was changed in COPD group containing 219 COPD-related CpG sites in total. Notably, 27 CpG sites of FOXO3 gene showed a lower False Discovery Rate (FDR) and higher methylation difference values. Also, some variable DNA methylation is associated with the severity of COPD. Additionally, of the 219 COPD-related CpG sites, 147 CpG sites were not related to smoking.
These results identified that the mRNA expression and DNA methylation level of aging-related genes were changed in male COPD patients, which provides a molecular link between aging and COPD. The identified CpG markers are associated with the severity of COPD and provide new insights into the prediction and identification of COPD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Germline alterations in the breast cancer susceptibility genes type 1 and 2,
and
, predispose individuals to hereditary cancers, including breast, ovarian, prostate, pancreatic, and stomach cancers. ...Accumulating evidence suggests inherited genetic susceptibility to lung cancer. The present study aimed to survey the prevalence of pathogenic germline
mutations (
) and explore the potential association between
and disease onset in Chinese advanced non-small cell lung cancer (NSCLC) patients.
A total of 6,220 NSCLC patients were screened using capture-based ultra-deep targeted sequencing to identify patients harboring germline
/
mutations.
Out of the 6,220 patients screened, 1.03% (64/6,220) of the patients harbored the pathogenic
, with
mutations being the most pr edominant mutations (49/64, 76.5%). Patients who developed NSCLC before 50 years of age were more likely to carry
(
= 0.036). Among the patients harboring classic lung cancer driver mutations, those with concurrent
were significantly younger than those harboring the wild-type
(
= 0.029). By contrast, the age of patients with or without concurrent
was comparable to those of patients without the driver mutations (
= 0.972). In addition, we identified
-mutant patients with concurrent g
who showed comparable progression-free survival but significantly longer overall survival (
= 0.002) compared to
-mutant patients with wild-type germline
.
Overall, our study is the largest survey of the prevalence of pathogenic
in advanced Chinese NSCLC patients. Results suggested a lack of association between germline
status and treatment outcome of EGFR-TKI. In addition, results showed a positive correlation between pathogenic
and an early onset of NSCLC.
Recent studies have indicated that monocyte chemoattractant protein-1 (MCP-1) plays an important role in the initiation and progression of ischaemic heart disease. However, no previous research has ...investigated the correlation between serum MCP-1 levels and early changes in myocardial function in patients with ST-segmental elevation myocardial infarction (STEMI) after primary percutaneous coronary intervention (PCI).
A total of 87 STEMI patients who had undergone a successful primary PCI were consecutively recruited. All the patients included in this study were grouped into two subgroups according to the median value of MCP-1 upon admission. An early change in left ventricular ejection fraction (LVEF) was defined as (LVEF at 3 months post-STEMI)-(LVEF at 2 days post-STEMI).
Serum MCP-1 levels increased gradually over time during the first 72 h after the onset of STEMI. The concentration of hypersensitive cardiac troponin I (hs-cTnI) upon admission as well as at 24 h and 72 h after primary PCI, especially the peak hs-cTnI concentration, declined significantly in the low admission MCP-1 group. As continuous variable, admission MCP-1 also correlated positively with admission hs-cTnI, hs-cTnI at 24 h after primary PCI, and peak hs-cTnI. Additionally, the absolute early change in LVEF improved markedly in the low admission MCP-1 group (3.77% ± 6.05% vs - 0.18% ± 7.69%, p = 0.009) compared to that in the high admission MCP-1 group. Most importantly, the global LVEF in the low admission MCP-1 group also improved significantly at 3 months compared to baseline LVEF (55.79% ± 7.05% vs 59.60% ± 6.51%, p = 0.011), while an improvement in global LVEF was not observed in the high admission MCP-1 group. Furthermore, as a continuous variable, the MCP-1 level up admission also correlated negatively with early changes in LVEF (r = - 0.391, p = 0.001). After assessment by multiple linear regression analysis, the MCP-1 level upon admission remained correlated with early changes in LVEF beta = - 0.089, 95% CI (- 0.163 to - 0.015), p = 0.020.
MCP-1 upon admission not only correlated positively with hs-cTnI at different time points and peak hs-cTnI, but also associated inversely with early improvements in myocardial function in patients with first STEMI. So we speculated that suppression the expression of MCP-1 via various ways may be a promising therapeutic target in myocardial I/R injury in the future.
PDF
