- 作者列表："Pinsky P","Gierada DS
OBJECTIVE:Non-calcified nodules (NCNs) associated with false positive low-dose CT (LDCT) lung cancer screens have been attributed to various causes. Some, however, may represent lung cancer precursors. An association of NCNs with long-term lung cancer risk would provide indirect evidence of some NCNs being cancer precursors. METHODS:LDCT arm participants in the National Lung Screening Trial (NLST) received LDCT screens at baseline and years 1-2. The relationship between NCNs found on LDCT screens and subsequent lung cancer diagnosis over different time periods was examined at the person and lobe level. For the latter, a lobe had a cancer outcome only if the cancer was located in the lobe. Separate analyses were performed on baseline and post-baseline LDCT findings; for the latter, those with baseline NCNs were excluded and only new (non-pre-existing) NCNs examined. Raw and adjusted rate-ratios (RRs) were computed for presence of NCNs and subsequent lung cancer risk; adjusted RRs controlled for demographic and smoking factors. RESULTS:26,309 participants received the baseline LDCT screen. Over median 11.3 years follow-up, 1675 lung cancers were diagnosed. Adjusted RRs for time periods 0-4, 4-8 and 8-12 years following the baseline screen were 5.1 (95 % CI:4.4-5.9), 1.5 (95 % CI:1.3-1.9) and 1.5 (95 % CI:1.2-1.8) at the person-level and 14.7 (95 % CI:12.6-17.2), 2.6 (95 % CI: 2.0-3.4) and 2.2 (95 % CI:1.6-2.9) at the lobe-level. 18,585 participants were included in the post-baseline analysis. Adjusted RRs for periods 0-4, 4-8 and 8-11 years were 5.6 (95 % CI: 4.5-7.0), 1.9 (95 % CI: 1.3-2.7) and 1.6 (95 % CI: 0.9-2.9) at the person-level and 19.6 (95 % CI:14.9-25.3), 2.5 (95 % CI:1.3-4.7) and 3.3 (95 % CI:1.4-7.6) at the lobe-level. Raw RRs were similar. CONCLUSION:NCNs are associated with excess long-term lung cancer risk, suggesting that some may be lung cancer precursors.
目的: 与低剂量 CT (LDCT) 肺癌筛查假阳性相关的非钙化结节 (NCNs) 被归因于各种原因。然而，一些可能代表肺癌的前体。NCNs 与长期肺癌风险的关联将提供一些 NCNs 是癌症前体的间接证据。 方法: 国家肺筛查试验 (NLST) 的 LDCT 组参与者在基线和 1-2 年接受了 LDCT 筛查。在人与叶水平检查 LDCT 筛查发现的 NCNs 与随后不同时间段肺癌诊断的关系。对于后者，只有当癌症位于肺叶时，肺叶才会有癌症结果。对基线和基线后 LDCT 结果进行单独分析; 对于后者，排除基线 NCNs 的患者，仅检查新的 (非先前存在的) NCNs。计算 NCNs 存在和随后肺癌风险的原始和校正 RRs (RRs); 校正 RRs 控制人口统计学和吸烟因素。 结果: 26,309 名参与者接受了基线 LDCT 筛查。超过中位数 11.3 年的随访，1675 例肺癌被诊断。基线筛查后 0-4 、 4-8 和 8-12 年时间段的校正 rr 分别为 5.1 (95% CI: 4.4-5.9) 、 1.5 (95% CI: 1.3-1.9) 和 1.5 (95% CI: 1.2-1.8) 在 person-level 和 14.7 (95% CI: 12.6-17.2)，2.6 (95% CI: 2.0-3.4) 和 2.2 (95% CI: 1.6-2.9)在肺叶水平。18,585 名参与者被纳入基线后分析。0-4 、 4-8 和 8-11 年期间的调整 rr 分别为 5.6 (95% CI: 4.5-7.0) 、 1.9 (95% CI: 1.3-2.7) 和 1.6 (95% CI: 0.9-2.9) 在人一级和 19.6 (95% CI: 14.9-25.3)，2.5 (95% CI: 1.3-4.7) 和 3.3 (95% CI: 1.4-7.6)在肺叶水平。原始 RRs 相似。 结论: NCNs 与过量的长期肺癌风险相关，提示一些可能是肺癌的前体。
METHODS:BACKGROUND AND PURPOSE:A critical role for sphingosine kinase/sphingosine-1-phosphate (S1P) pathway in the control of airway function has been demonstrated in respiratory diseases. Here, we address S1P contribution in a mouse model of mild chronic obstructive pulmonary disease (COPD). EXPERIMENTAL APPROACH:C57BL/6J mice have been exposed to room air or cigarette smoke up to 11 months and killed at different time points. Functional and molecular studies have been performed. KEY RESULTS:Cigarette smoke caused emphysematous changes throughout the lung parenchyma coupled to a progressive collagen deposition in both peribronchiolar and peribronchial areas. The high and low airways showed an increased reactivity to cholinergic stimulation and α-smooth muscle actin overexpression. Similarly, an increase in airway reactivity and lung resistances following S1P challenge occurred in smoking mice. A high expression of S1P, Sph-K2 , and S1P receptors (S1P2 and S1P3 ) has been detected in the lung of smoking mice. Sphingosine kinases inhibition reversed the increased cholinergic response in airways of smoking mice. CONCLUSIONS AND IMPLICATIONS:S1P signalling up-regulation follows the disease progression in smoking mice and is involved in the development of airway hyperresponsiveness. Our study defines a therapeutic potential for S1P inhibitors in management of airways hyperresponsiveness associated to emphysema in smokers with both asthma and COPD.
METHODS::The interim results from this 90-day multi-dose, inhalation toxicology study with life-time post-exposure observation has shown an important fundamental difference in persistence and pathological response in the lung between brake dust derived from brake-pads manufactured with chrysotile, TiO2 or chrysotile alone in comparison to the amphiboles, crocidolite and amosite asbestos. In the brake dust exposure groups no significant pathological response was observed at any time. Slight macrophage accumulation of particles was noted. Wagner-scores, were from 1 to 2 (1 = air-control group) and were similar to the TiO2 group. Chrysotile being biodegradable, shows a weakening of its matrix and breaking into short fibers & particles that can be cleared by alveolar macrophages and continued dissolution. In the chrysotile exposure groups, particle laden macrophage accumulation was noted leading to a slight interstitial inflammatory response (Wagner-score 1-3). There was no peribronchiolar inflammation and occasional very slight interstitial fibrosis. The histopathology and the confocal analyses clearly differentiate the pathological response from amphibole asbestos, crocidolite and amosite, compared to that from the brake dust and chrysotile. Both crocidolite and amosite induced persistent inflammation, microgranulomas, and fibrosis (Wagner-scores 4), which persisted through the post exposure period. The confocal microscopy of the lung and snap-frozen chestwalls quantified the extensive inflammatory response and collagen development in the lung and on the visceral and parietal surfaces. The interim results reported here, provide a clear basis for differentiating the effects from brake dust exposure from those following amphibole asbestos exposure. The subsequent results through life-time post-exposure will follow.
METHODS::The respiratory tract is lined by a pseudo-stratified epithelium from the nose to terminal bronchioles. This first line of defense of the lung against external stress includes five main cell types: basal, suprabasal, club, goblet and multiciliated cells, as well as rare cells such as ionocytes, neuroendocrine and tuft/brush cells. At homeostasis, this epithelium self-renews at low rate but is able of fast regeneration upon damage. Airway epithelial cell lineages during regeneration have been investigated in the mouse by genetic labeling, mainly after injuring the epithelium with noxious agents. From these approaches, basal cells have been identified as progenitors of club, goblet and multiciliated cells, but also of ionocytes and neuroendocrine cells. Single-cell RNA sequencing, coupled to lineage inference algorithms, has independently allowed the establishment of comprehensive pictures of cell lineage relationships in both mouse and human. In line with genetic tracing experiments in mouse trachea, studies using single-cell RNA sequencing (RNAseq) have shown that basal cells first differentiate into club cells, which in turn mature into goblet cells or differentiate into multiciliated cells. In the human airway epithelium, single-cell RNAseq has identified novel intermediate populations such as deuterosomal cells, 'hybrid' mucous-multiciliated cells and progenitors of rare cells. Novel differentiation dynamics, such as a transition from goblet to multiciliated cells have also been discovered. The future of cell lineage relationships in the respiratory tract now resides in the combination of genetic labeling approaches with single-cell RNAseq to establish, in a definitive manner, the hallmarks of cellular lineages in normal and pathological situations.