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Radiologic Features of Nodules Attached to the Mediastinal or Diaphragmatic Pleura at Low-Dose CT for Lung Cancer Screening
Not provided.
A 20-year Follow-up of the International Early Lung Cancer Action Program (I-ELCAP)
Not provided.
KRAS[superscript Q61H] Preferentially Signals through MAPK in a RAF Dimer-Dependent Manner in Non-Small Cell Lung Cancer
Abstract not provided
RNA Phage delivery to lung tissue for protection against airborne illness
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DYNAMICS OF LUNG MACROPHAGE ACTIVATION IN RESPONSE TO INFECTION: INSIGHTS FROM GENE EXPRESSION ANALYSIS
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Immolative cell-penetrating complexes for nucleic acid delivery to the lung
There are provided herein, inter alia, cationic amphipathic polymers, complexes, and compositions comprising same, and methods for their use including for the delivery of therapeutic, diagnostic and imaging agents, including nucleic acids, into a cell. The complexes, compositions and methods may facilitate delivery and targeted release of the therapeutic, diagnostic and imaging agents to particular cell types and tissues.
Influence of the irradiated pulmonary microenvironment on macrophage and T cell dynamics
The lung is sensitive to radiation, which increases the risk of normal tissue toxicity following radiation therapy. Adverse outcomes include pneumonitis and pulmonary fibrosis, which are thought to result from dysregulated intercellular communication within the pulmonary microenvironment. Macrophage accumulation in the lung following radiation exposure is implicated in these pathogenic outcomes. Here we investigate the role of the microenvironment in macrophage and T cell dynamics. Materials and methods C57Bl/6 mice received 6Gyx5 x-ray irradiation to the right lung. Macrophage and T cell dynamics were investigated in ipsilateral right lungs, contralateral left lungs and compared to those from non-irradiated control subjects at 4-26wk post exposure. Lungs were evaluated by flow cytometry, histology and proteomics. Results In uni-lung irradiated subjects, focal regions of macrophage accumulation were noted in both lungs by 8wk, however fibrotic lesions were observed only in ipsilateral lungs by 26wk. Both infiltrating and alveolar macrophages populations transiently expanded in both lungs, however a transitional CD11b+ alveolar macrophage population persisted only in ipsilateral lungs and expressed lower CD206. Concurrently, arginase-1+ macrophages were noted within areas of macrophage accumulation in ipsilateral but not contralateral lungs at 8 and 26wk post exposure, while CD206+ macrophages were absent from these accumulations. While CD8+ T cells were present in both lungs of irradiated subjects, T regulatory cells were only increased in ipsilateral lungs. Unbiased proteomics analysis of immune cells revealed a substantial number of differentially expressed proteins in ipsilateral lungs when compared to either contralateral or non-irradiated lungs, as well as between contralateral lungs from irradiated subjects and non-irradiated controls. Conclusions Pulmonary macrophage and T cell dynamics are impacted by the microenvironmental conditions that develop in the lung following radiation exposure, both locally and systemically. Our findings demonstrate that while macrophages and T cells infiltrate and expand in both lungs, they diverge phenotypically depending on their environment.
Repeated exposure to eucalyptus wood smoke alters pulmonary gene and metabolic profiles in male Long-Evans rats
Abstract Exposure to wildfire smoke is associated with both acute and chronic cardiopulmonary illnesses, which are of special concern for wildland firefighters who experience repeated exposure to wood smoke. It is necessary to better understand the underlying pathophysiology by which wood smoke exposure increases pulmonary disease burdens in this population. We hypothesize that wood smoke exposure produces pulmonary dysfunction, lung inflammation, and gene expression profiles associated with future pulmonary complications. Male Long-Evans rats were intermittently exposed to smoldering eucalyptus wood smoke at 2 concentrations, low (11.0 ± 1.89 mg/m3) and high (23.7 ± 0.077 mg/m3), over a 2-week period. Whole-body plethysmography was measured intermittently throughout. Lung tissue and lavage fluid were collected 24 h after the final exposure for transcriptomics and metabolomics. Increasing smoke exposure upregulated neutrophils and select cytokines in the bronchoalveolar lavage fluid. In total, 3446 genes were differentially expressed in the lungs of rats in the high smoke exposure and only 1 gene in the low smoke exposure (Cd151). Genes altered in the high smoke group reflected changes to the Eukaryotic Initiation Factor 2 stress and oxidative stress responses, which mirrored metabolomics analyses. xMWAS-integrated analysis revealed that smoke exposure significantly altered pathways associated with oxidative stress, lung morphogenesis, and tumor proliferation pathways. These results indicate that intermittent, 2-week exposure to eucalyptus wood smoke leads to transcriptomic and metabolic changes in the lung that may predict future lung disease development. Collectively, these findings provide insight into cellular signaling pathways that may contribute to the chronic pulmonary conditions observed in wildland firefighters.
Mortality among Tennessee Eastman Corporation (TEC) uranium processing workers, 1943–2019
Background: There are few occupational studies of women exposed to ionizing radiation. During World War II, the Tennessee Eastman Corporation (TEC) operated an electromagnetic field separation facility of 1152 calutrons to obtain enriched uranium (235U) used for the Hiroshima atomic bomb. Thousands of women were involved in these operations. Materials and methods: We report a new study was conducted of 13,951 women and 12,699 men employed at TEC between 1943 and 1947 for at least 90 days. Comprehensive dose reconstruction techniques were used to estimate lung doses from the inhalation of uranium dust based on airborne measurements. Vital status through 2018/2019 was obtained from the National Death Index, Social Security Death Index, Tennessee death records and online public record databases. Analyses included standardized mortality ratios (SMRs) and Cox proportional hazards models. Results: Most workers were hourly (77.7%), white (95.6%), born before 1920 (58.3%), worked in dusty environments (57.0%), and had died (94.9%). Vital status was confirmed for 97.4% of the workers. Women were younger than men when first employed: mean ages 25.0 years and 33.0 years, respectively. The estimated mean absorbed dose to the lung was 32.7 mGy (max 1048 mGy) for women and 18.9 mGy (max 501 mGy) for men. The mean dose to thoracic lymph nodes (TLNs) was 127 mGy. Statistically significant SMRs were observed for lung cancer (SMR 1.25; 95% CI 1.19, 1.31; n = 1654), nonmalignant respiratory diseases (NMRDs) (1.23; 95% CI 1.19, 1.28; n = 2585), and cerebrovascular disease (CeVD) (1.13; 95% CI 1.08, 1.18; n = 1945). For lung cancer, the excess relative rate (ERR) at 100 mGy (95% CI) was 0.01 (–0.10, 0.12; n = 652) among women, and –0.15 (–0.38, 0.07; n = 1002) among men based on a preferred model for men with lung doses <300 mGy. NMRD and non-Hodgkin lymphoma were not associated with estimated absorbed dose to the lung or TLN. Conclusions: There was little evidence that radiation increased the risk of lung cancer, suggesting that inhalation of uranium dust and the associated high-LET alpha particle exposure to lung tissue experienced over a few years is less effective in causing lung cancer than other types of exposures. There was no statistically significant difference in the lung cancer risk estimates between men and women. The elevation of certain causes of death such as CeVD is unexplained and will require additional scrutiny of workplace or lifestyle factors given that radiation is an unlikely contributor since only the lung and lymph nodes received appreciable dose.
MCL1 inhibition enhances the efficacy of docetaxel against airway-derived squamous cell carcinoma cells
Highlights: • Authentic squamous cell carcinoma (SqCC) cell lines of the lung are sparse. • HARA lung SqCC cells depend highly on MCL1 for survival in vitro and in vivo. • MCL1-silenced HARA cells decline in number upon docetaxel (DTX) exposure. • High MCL1 mRNA expression is linked with shorter survival in lung SqCC patients. • MCL1 depletion + DTX is highly effective against Detroit 562 pharyngeal SqCC cells. MCL1 is an anti-apoptotic BCL2 family member that is often overexpressed in various malignant tumors. However, few reports have described the role of MCL1 in squamous cell carcinoma (SqCC) derived from airways including the lung. In this study, we examined whether MCL1 could be a novel druggable target for airway-derived SqCC, for which effective molecular targeted drugs are unavailable. We searched the Kaplan–Meier Plotter database and found that high MCL1 mRNA expression was significantly associated with shorter survival in patients with lower airway (lung) or upper airway (head and neck) derived SqCC. We also explored the Expression Atlas database and learned that authentic lung SqCC cell lines expressing both TP63 and KRT5 mRNA were extremely sparse among the publicly available “lung SqCC cell lines”, with an exception being HARA cells. HARA cells were highly dependent on MCL1 for survival, and MCL1-depleted cells were not able to grow, and even declined in number, upon docetaxel (DTX) exposure in vitro and in vivo. Similar in vitro experimental findings, including those in a 3D culture model, were also obtained using Detroit 562 pharyngeal SqCC cells. These findings suggested that combined treatment with MCL1 silencing plus DTX appears highly effective against airway-derived SqCC.
AAPM Truth‐based CT (TrueCT) reconstruction grand challenge
Background: This Special Report summarizes the 2022, AAPM grand challenge on Truth-based CT image reconstruction. Purpose: To provide an objective framework for evaluating CT reconstruction methods using virtual imaging resources consisting of a library of simulated CT projection images of a population of human models with various diseases. Methods: Two hundred unique anthropomorphic, computational models were created with varied diseases consisting of 67 emphysema, 67 lung lesions, and 66 liver lesions. The organs were modeled based on clinical CT images of real patients. The emphysematous regions were modeled using segmentations from patient CT cases in the COPDGene Phase I dataset. For the lung and liver lesion cases, 1–6 malignant lesions were created and inserted into the human models, with lesion diameters ranging from 5.6 to 21.9 mm for lung lesions and 3.9 to 14.9 mm for liver lesions. The contrast defined between the liver lesions and liver parenchyma was 82 ± 12 HU, ranging from 50 to 110 HU. Similarly, the contrast between the lung lesions and the lung parenchyma was defined as 781 ± 11 HU, ranging from 725 to 805 HU. For the emphysematous regions, the defined HU values were −950 ± 17 HU ranging from −918 to −979 HU. The developed human models were imaged with a validated CT simulator. The resulting CT sinograms were shared with the participants. The participants reconstructed CT images from the sinograms and sent back their reconstructed images. Further, the reconstructed images were then scored by comparing the results against the corresponding ground truth values. The scores included both task-generic (root mean square error [RMSE] and structural similarity matrix [SSIM]), and task-specific (detectability index [d’] and lesion volume accuracy) metrics. For the cases with multiple lesions, the measured metric was averaged across all the lesions. To combine the metrics with each other, each metric was normalized to a range of 0 to 1 per disease type, with “0” and “1” being the worst and best measured values across all cases of the disease type for all received reconstructions. Results: The True-CT challenge attracted 52 participants, out of which 5 successfully completed the challenge and submitted the requested 200 reconstructions. Across all participants and disease types, SSIM absolute values ranged from 0.22 to 0.90, RMSE from 77.6 to 490.5 HU, d’ from 0.1 to 64.6, and volume accuracy ranged from 1.2 to 753.1 mm3. The overall scores demonstrated that participant “A” had the best performance in all categories, except for the metrics of d’ for lung lesions and RMSE for liver lesions. Participant “A” had an average normalized score of 0.41 ± 0.22, 0.48 ± 0.32, and 0.42 ± 0.33 for the emphysema, lung lesion, and liver lesion cases, respectively. Conclusions: The True-CT challenge successfully enabled objective assessment of CT reconstructions with the unique advantage of access to a diverse population of diseased human models with known ground truth. This study highlights the significant potential of virtual imaging trials in objective assessment of medical imaging technologies.
DYNC1H1 regulates NSCLC cell growth and metastasis by IFN-γ-JAK-STAT signaling and is associated with an aberrant immune response
Highlights: • DYNC1H1 is upregulated and its high expression predicted poor outcomes in NSCLC. • Loss of function of DYNC1H1 inhibits cell growth and metastasis of NSCLC cells in vitro. • DYNC1H1 knockdown inhibited metastasis of NSCLC cells in vivo. • DYNC1H1 loss of function suppresses IFN-γ-JAK-STAT signaling pathway in NSCLC. • DYNC1H1 expression is correlated with aberrant immune response in NSCLC indicated by analysis of TCGA immune data. It is urgent to identify new biomarkers and therapeutic targets to ameliorate the clinical prognosis of patients with lung cancer. The functional significance and molecular mechanism of dynein cytoplasmic 1 heavy chain 1 (DYNC1H1) in nonsmall cell lung cancer (NSCLC) progression is still elusive. In our current study, publicly available data and Western blotting experiments confirmed that DYNC1H1 expression was upregulated in lung cancer samples compared with noncancerous samples. Quantitative real-time PCR (qPCR) results indicated that high DYNC1H1 expression in lung cancer tissues was significantly associated with clinical tumor stage and distal metastasis; moreover, its high expression was negatively correlated with prognosis. Functional experiments demonstrated that DYNC1H1 loss of function caused a significant decrease in cell viability and cell proliferative ability, inhibition of the cell cycle, and promotion of both migration potential and invasion potential in vitro. Animal experiments by tail vein injection of lung cancer cells showed that DYNC1H1 knockdown significantly decreased lung cancer metastasis. Mechanistically, the results from a human protein array showed changes in the IFN-γ-JAK-STAT signaling pathway, and analysis of The Cancer Genome Atlas (TCGA) immune data demonstrated that disturbance of the immune microenvironment might be involved in the impaired growth and metastatic ability mediated by DYNC1H1 loss in NSCLC. DYNC1H1 might serve as a promising biological marker of prognosis and a potential clinical therapeutic target for patients with NSCLC.
Pulmonary ACE2 expression in neonatal and adult rats
Children show a distinct presentation of COVID‐19, characterized by a lower incidence and mild phenotype, but the reason for this is still unknown. The angiotensin‐converting enzyme 2 (ACE2) functions as the primary cell entry receptor for Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and is thought to cause distinct clinical features between children and old people. The primary purpose of this study was to determine whether differences exist in the level of expression and distribution of ACE2 between neonatal and adult rat lungs. The lung tissues from rats of various ages were used to investigate the expression patterns of ACE2. Western blot, immunohistochemistry, and immunofluorescence were used to quantify or identify the localization of ACE2 in rat lungs. ACE2 was homogenously expressed in fewer alveolar type II (AT2) cells in the neonatal lung, with no polarization to the alveolar space and additional expression in pulmonary endothelium when compared to adult rat lungs. These findings suggest that the patterns of ACE2 distribution and cellular localization in rat lungs change with age.
Shift in Peaks of PAH-Associated Health Risks From East Asia to South Asia and Africa in the Future
Lung cancer risk from exposure to ambient polycyclic aromatic hydrocarbons (PAHs) is expected to change significantly by 2050 compared to 2008 due to changes in climate and emissions. Integrating a global atmospheric chemistry model, a lung cancer risk model, and plausible future emissions trajectories of PAHs, we assess how global PAHs and their associated lung cancer risk will likely change in the future. Benzo(a)pyrene (BaP) is used as an indicator of cancer risk from PAH mixtures. From 2008 to 2050, the population-weighted global average BaP concentrations under all RCPs consistently exceeded the WHO-recommended limits, primarily attributed to residential biofuel use. Peaks in PAH-associated incremental lifetime cancer risk shift from East Asia (4 × 10 –5 ) in 2008 to South Asia (mostly India, 2–4 × 10 –5 ) and Africa (1–2 × 10 –5 ) by 2050. In the developing regions of Africa and South Asia, PAH-associated lung cancer risk increased by 30–64% from 2008 to 2050, due to increasing residential energy demand in households for cooking, heating, and lighting, the continued use of traditional biomass use, increases in agricultural waste burning, and forest fires, accompanied by rapid population growth in these regions. Due to more stringent air quality policies in developed countries, their PAH lung cancer risk substantially decreased by ~80% from 2008 to 2050. Climate change is likely to have minor effects on PAH lung cancer risk compared to the impact of emissions. Future policies, therefore, need to consider efficient combustion technologies that reduce air pollutant emissions, including incomplete combustion products such as PAH.
An intranasal recombinant NDV-BRSV F opt vaccine is safe and reduces lesion severity in a colostrum-deprived calf model of RSV infection
Human respiratory syncytial virus (HRSV) is a major cause of severe lower respiratory tract disease in infants and the elderly, yet no safe, effective vaccine is commercially available. Closely related bovine RSV (BRSV) causes respiratory disease in young calves, with many similar features to those seen in HRSV. We previously showed that a Newcastle disease virus (NDV)-vectored vaccine expressing the F glycoprotein of HRSV reduced viral loads in lungs of mice and cotton rats and protected from HRSV. However, clinical signs and pathogenesis of disease in laboratory animals following HRSV infection differs from that observed in human infants. Thus, we examined whether a similar vaccine would protect neonatal calves from BRSV infection. Codon-optimized rNDV vaccine (rNDV-BRSV F opt ) was constructed and administered to colostrum-deprived calves. The rNDV-BRSV F opt vaccine was well-tolerated and there was no evidence of vaccine-enhanced disease in the upper airways or lungs of these calves compared to the non-vaccinated calves. We found two intranasal doses reduces severity of gross and microscopic lesions and decreases viral load in the lungs. Furthermore, serum neutralizing antibodies were generated in vaccinated calves. Finally, reduced lung CXC chemokine levels were observed in vaccinated calves after BRSV challenge. In summary, we have shown that rNDV-BRSV F opt vaccine is safe in colostrum-deprived calves, and is effective in reducing lung lesions, and decreasing viral load in upper respiratory tract and lungs after challenge.
Pre- and post-treatment image-based dosimetry in 90 Y-microsphere radioembolization using the TOPAS Monte Carlo toolkit
Objective.To evaluate the pre-treatment and post-treatment imaging-based dosimetry of patients treated with 90Y-microspheres, including accurate estimations of dose to tumor, healthy liver and lung. To do so, the Monte Carlo (MC) TOPAS platform is in this work extended towards its utilization in radionuclide therapy. Approach. In this study, five patients treated at the Massachusetts General Hospital were selected for this study. All patients had data for both pre-treatment SPECT-CT imaging using 99mTc-MAA as a surrogate of the 90Y-microspheres treatment and SPECT-CT imaging immediately after the 90Y activity administration. Pre- and post-treatment doses were computed with TOPAS using the SPECT images to localize the source positions and the CT images to account for tissue inhomoegeneities. We compared our results with analytical calculations following the voxel-based MIRD scheme. Main results. TOPAS results largely agreed with the MIRD-based calculations in soft tissue regions: the average difference in mean dose to the liver was 0.14 Gy GBq -1 (2.6%). However, dose distributions in the lung differed considerably: absolute differences in mean doses to the lung ranged from 1.2 to 6.3 Gy GBq -1 and relative differences from 153% to 231%. We also found large differences in the intra-hepatic dose distributions between pre- and post-treatment imaging, but only limited differences in the pulmonary dose. Significance. Doses to lung were found to be higher using TOPAS with respect to analytical calculations which may significantly underestimate dose to the lung, suggesting the use of MC methods for 90Y dosimetry. According to our results, pre-treatment imaging may still be representative of dose to lung in these treatments.
Reduction in total and major cause-specific mortality from tobacco smoking cessation: a pooled analysis of 16 population-based cohort studies in Asia
Little is known about the time course of mortality reduction following smoking cessation in Asians who have smoking behaviours distinct from their Western counterparts. We evaluated the level of reduction in all-cause, cardiovascular disease (CVD) and lung cancer mortality by years since quitting smoking, in Asia. Using Cox regression, we analysed individual participant data (n = 709 151) from 16 prospective cohorts conducted in China, Japan, Korea/Singapore, and India/Bangladesh, separately by cohorts. Cohort-specific hazard ratios (HRs) were combined using a random-effects meta-analysis. During a mean follow-up of 12.0 years, 108 287 deaths were ascertained—35 658 from CVD and 7546 from lung cancer. Among Asian men, a dose-response relationship of risk reduction in deaths from all causes, CVD and lung cancer was observed with an increase in years after smoking cessation. Compared with never smokers, however, all-cause and CVD mortality among former smokers remained elevated 10–14 years after quitting [multivariable-adjusted HR (95% confidence interval (CI) = 1.25 (1.13–1.37) and 1.20 (1.02–1.41), respectively]. Lung cancer mortality stayed almost 2-fold higher than among never smokers 15–19 years after smoking cessation [1.97 (1.41–2.73)], particularly among former heavy smokers [2.62 (1.71–4.00)]. Women who quitted for ≥5 years retained a significantly elevated mortality from all causes, CVD and lung cancer. Overall patterns of the cessation-mortality associations were similar across countries. Our findings suggest that adverse effects of tobacco smoking persist for an extended time period, even for more than two decades, which is beyond the time windows defined in current clinical guidelines for risk assessment of lung cancer and CVD.