Paraquat Poisoning—Lung Transplantation

A 15-year-old boy ingested a mouthful of paraquat and developed severe respiratory distress. Treatment included the transplantation of one lung, but subsequently changes developed in the graft which are thought to have been due to paraquat, and the patient died two weeks after the operationThe dangers of keeping poisonous substances in incorrectly labelled bottles has once again been demonstrated, while the pattern of paraquat poisoning, especially the development of proliferative alveolitis and terminal bronchiolitis, is confirmed.Immediate forced diuresis followed by haemodialysis is necessary to remove paraquat, thereby perhaps avoiding initiation of the changes in the lungs. The technical feasibility of human lung transplantation has again been demonstrated. It has also been shown that infection does not necessarily pose an insuperable problem, at any rate if, as in the case described, there was no preoperative pulmonary infection in either recipient or donor.     

Direct Transformation of Lung Microenvironment by Interferon-α Treatment Counteracts Growth of Lung Metastasis of Hepatocellular Carcinoma

Background

Interferon (IFN)-α is effective in inhibiting tumor growth and metastasis of hepatocellular carcinoma (HCC). However, the biologic mechanisms of IFN-α treatment in lung metastasis are not yet clear.

Methods

The effect of IFN-α treatment was studied by using an orthotopic xenograft model and measuring tumor size and lung metastasis. Pretreatment with IFN-α before implantation of tumor was done to explore the effect of IFN-α on lung tissues. Cytokines and macrophages were measured by immunohistochemistry and/or PCR assay, using human origin or mouse origin primers to differentiate the sources. Circulating tumor cells (CTCs) were also assayed by flow cytometry.

Results

IFN-α treatment did not decrease the number of CTCs (0.075%±0.020% versus 0.063%±0.018%, P = 0.574, IFN-α–treated versus control groups), but did decrease the number and size of lung metastasis (number: 1.75±1.0 versus 28.0±6.3, P = 0.008; size [pixels]: 116.8±72.2 versus 5226.4±1355.7, P = 0.020), and inhibited macrophage infiltration (0.20%±0.04% versus 1.36%±0.21%, P = 0.0058) and alteration of matrix metalloproteinase (MMP)-9 expression (mean integrated optical density (IOD): 5.1±1.7 versus 21.9±0.4, P<0.000) in the lung, which was independent of the primary tumor.

Conclusion

IFN-α inhibited lung metastasis by directly modulating the lung microenvironment.     

Is Genetic Background Important in Lung Cancer Survival?

Background

In lung cancer, a patient''s survival is poor with a wide variation in survival within the stage of disease. The aim of this study was to investigate the familial concordance in lung cancer survival by means of analyses of pairs with different degrees of familial relationships.

Methods

Our population-based Swedish family database included three million families and over 58 100 lung cancer patients. We modelled the proband (parent, sibling, spouse) survival utilizing a multivariate proportional hazard (Cox) model adjusting for possible confounders of survival. Subsequently, the survival in proband''s relative (child, sibling, spouse) was analysed with a Cox model.

Findings

By use of Cox modelling with 5 years follow-up, we noted a decreased hazard ratio for death in children with good parental survival (Hazard Ratio [HR] = 0.71, 95% CI = 0.51 to 0.99), compared to those with poor parental survival. Also for siblings, a very strong protective effect was seen (HR = 0.14, 95% CI = 0.030 to 0.65). Finally, in spouses no correlation in survival was found.

Interpretation

Our findings suggest that genetic factors are important in lung cancer survival. In a clinical setting, information on prognosis in a relative may be vital in foreseeing the survival in an individual newly diagnosed with lung cancer. Future molecular studies enhancing the understanding of the underlying mechanisms and pathways are needed.     

Lung cancer and oncolytic virotherapy——enemy's enemy

Lung cancer is one of the malignant tumors that seriously threaten human health worldwide, while the covid-19 virus has become people's nightmare after the coronavirus pandemic. There are too many similarities between cancer cells and viruses, one of the most significant is that both of them are our enemies. The strategy to take the advantage of the virus to beat cancer cells is called Oncolytic virotherapy. When immunotherapy represented by immune checkpoint inhibitors has made remarkable breakthroughs in the clinical practice of lung cancer, the induction of antitumor immunity from immune cells gradually becomes a rapidly developing and promising strategy of cancer therapy. Oncolytic virotherapy is based on the same mechanisms that selectively kill tumor cells and induce systemic anti-tumor immunity, but still has a long way to go before it becomes a standard treatment for lung cancer. This article provides a comprehensive review of the latest progress in oncolytic virotherapy for lung cancer, including the specific mechanism of oncolytic virus therapy and the main types of oncolytic viruses, and the combination of oncolytic virotherapy and existing standard treatments. It aims to provide new insights and ideas on oncolytic virotherapy for lung cancer.     

Tristetraprolin Mediates Radiation-Induced TNF-α Production in Lung Macrophages

The efficacy of radiation therapy for lung cancer is limited by radiation-induced lung toxicity (RILT). Although tumor necrosis factor-alpha (TNF-α) signaling plays a critical role in RILT, the molecular regulators of radiation-induced TNF-α production remain unknown. We investigated the role of a major TNF-α regulator, Tristetraprolin (TTP), in radiation-induced TNF-α production by macrophages. For in vitro studies we irradiated (4 Gy) either a mouse lung macrophage cell line, MH-S or macrophages isolated from TTP knockout mice, and studied the effects of radiation on TTP and TNF-α levels. To study the in vivo relevance, mouse lungs were irradiated with a single dose (15 Gy) and assessed at varying times for TTP alterations. Irradiation of MH-S cells caused TTP to undergo an inhibitory phosphorylation at Ser-178 and proteasome-mediated degradation, which resulted in increased TNF-α mRNA stabilization and secretion. Similarly, MH-S cells treated with TTP siRNA or macrophages isolated from ttp (−/−) mice had higher basal levels of TNF-α, which was increased minimally after irradiation. Conversely, cells overexpressing TTP mutants defective in undergoing phosphorylation released significantly lower levels of TNF-α. Inhibition of p38, a known kinase for TTP, by either siRNA or a small molecule inhibitor abrogated radiation-induced TNF-α release by MH-S cells. Lung irradiation induced TTP^Ser178 phosphorylation and protein degradation and a simultaneous increase in TNF-α production in C57BL/6 mice starting 24 h post-radiation. In conclusion, irradiation of lung macrophages causes TTP inactivation via p38-mediated phosphorylation and proteasome-mediated degradation, leading to TNF-α production. These findings suggest that agents capable of blocking TTP phosphorylation or stabilizing TTP after irradiation could decrease RILT.     

Lung Cancer: Are we up to the Challenge?

Lung cancer is the leading cause of cancer deaths worldwide among both men and women, with more than 1 million deaths annually. Non-small cell lung cancer (NSCLC) accounts for about 80% of all lung cancers.Although recent advances have been made in diagnosis and treatment strategies, the prognosis of NSCLC patients is poor and it is basically due to a lack of early diagnostic tools.However, in the last years genetic and biochemical studies have provided more information about the protein and gene's mutations involved in lung tumors. Additionally, recent proteomic and microRNA's approaches have been introduced to help biomarker discovery.Here we would like to discuss the most recent discoveries in lung cancer pathways, focusing on the genetic and epigenetic factors that play a crucial role in malignant cell proliferation, and how they could be helpful in diagnosis and targeted therapy.     

Commensal Microbiota Promote Lung Cancer Development via γδ T Cells

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Transforming Growth Factor β Signaling Overcomes Dasatinib Resistance in Lung Cancer

Lung cancer is the second most common cancer and the leading cause of cancer-related deaths. Despite recent advances in the development of targeted therapies, patients with advanced disease remain incurable, mostly because metastatic non-small cell lung carcinomas (NSCLC) eventually become resistant to tyrosine kinase inhibitors (TKIs). Kinase inhibitors have the potential for target promiscuity because the kinase super family is the largest family of druggable genes that binds to a common substrate (ATP). As a result, TKIs often developed for a specific purpose have been found to act on other targets. Drug affinity chromatography has been used to show that dasatinib interacts with the TGFβ type I receptor (TβR-I), a serine-threonine kinase. To determine the potential biological relevance of this association, we studied the combined effects of dasatinib and TGFβ on lung cancer cell lines. We found that dasatinib treatment alone had very little effect; however, when NSCLC cell lines were treated with a combination of TGFβ and dasatinib, apoptosis was induced. Combined TGFβ-1 + dasatinib treatment had no effect on the activity of Smad2 or other non-canonical TGFβ intracellular mediators. Interestingly, combined TGFβ and dasatinib treatment resulted in a transient increase in p-Smad3 (seen after 3 hours). In addition, when NSCLC cells were treated with this combination, the pro-apoptotic protein BIM was up-regulated. Knockdown of the expression of Smad3 using Smad3 siRNA also resulted in a decrease in BIM protein, suggesting that TGFβ-1 + dasatinib-induced apoptosis is mediated by Smad3 regulation of BIM. Dasatinib is only effective in killing EGFR mutant cells, which is shown in only 10% of NSCLCs. Therefore, the observation that wild-type EGFR lung cancers can be manipulated to render them sensitive to killing by dasatinib could have important implications for devising innovative and potentially more efficacious treatment strategies for this disease.     

Lung Cancer—Improved Cytologic Detection by Inducing Production of Sputum

The principle of producing bronchial lavage by deposition of large amounts of heated aerosol has resulted in a significantly greater yield of positive cytologic diagnosis of bronchogenic carcinoma than with repeated “volunteer” specimens of sputum. Positive pressure plus bronchodilators augments greater sputum volume.Using this technique, cases in which results of bronchoscopy and aspiration biopsy were negative for malignant change, were diagnosed cytologically.Application of this technique can sometimes detect early lung carcinoma before roentgenographic changes are detectable. Positive tests in clinically far advanced disease may prevent unnecessary surgical intervention.The simplicity of the technique, the freedom from adverse reactions, and its wide acceptance by the subjects tested, make it valuable in the diagnosis of lung cancer.     

Choline Transporters in Human Lung Adenocarcinoma： Expression and Functional Implications

Choline is an essential nutrient for cell survival and proliferation, however, the expression and function of choline transporters have not been well identified in cancer. In this study, we detected the mRNA and protein expression of organic cation transporter OCT3, carnitine/cation transporters OCTN 1 and OCTN2, and choline transporter-like protein CTL1 in human lung adenocarcinoma cell lines A549, H 1299 and SPC-A-1. Their expression pattern was further confirmed in 25 human primary adenocarcinoma tissues. The choline uptake in these cell lines was significantly blocked by CTL1 inhibitor, but only partially inhibited by OCT or OCTN inhibitors. The efficacy of these inhibitors on cell proliferation is closely correlated with their abilities to block choline transport. Under the native expression of these transporters, the total choline uptake was notably blocked by specific PI3K/AKT inhibitors. These results describe the expression of choline transporters and their relevant function in cell proliferation of human lung adenocarcinoma, thus providing a potential ＂choline-starvation＂ strategy of cancer interference through targeting choline transporters, especially CTL1.     

Trends in Lung Cancer Incidence Rates,Oklahoma 2005–2010

Purpose

Lung cancer is the second most frequently diagnosed cancer among men and women in the United States. With cigarette smoking causing the majority of cases, patterns in lung cancer are often monitored to understand the impact of anti-tobacco efforts. The purpose of this research was to investigate trends in lung cancer incidence rates for the period 2005–2010 in Oklahoma.

Methods

Data on Oklahoma’s incident cases of lung cancer (2005–2010) were obtained from the Centers for Disease Control and Prevention WONDER system. Annual percent change (APC) was calculated by linear regression to characterize trends in lung cancer incidence rates over time for the overall population, by gender, by age group, and by age group within gender. Rates were considered to increase or decrease if the p-value for trend was <0.05.

Results

From 2005 through 2010, lung cancer incidence rates declined from 81.96 to 68.19 per 100,000 population, with an APC of -3.58% (p-value: 0.0220). When subgroups were examined, declines were observed among all males (APC: -4.25%; p-value: 0.0270), males <65 years (APC: -5.32%; p-value: 0.0008), females <65 years (APC: -4.85%; p-value: 0.0044), and persons aged 55–64 years (APC: -6.38%; p-value: 0.0017).

Conclusions

Declines in lung cancer incidence rates occurred during 2005–2010 among the overall population and within select demographic groups in Oklahoma. Although trends were stable for several demographic groups, rates of lung cancer incidence were lower in 2010 compared to 2005. Continued evidence-based tobacco control efforts are needed to ensure further reductions in lung cancer incidence rates in the state of Oklahoma.     

Human–Human Hybridomas from Lung Cancer Patients Secrete Anti-DNA Antibodies

The effects of modification of the arginine/lysine ratio of dietary protein on the cholesterol kinetics were studied in male rats. Single amino acids (lysine to soybean protein and arginine to casein) were added to approximate the arginine/lysine ratio in different proteins. After acclimation to these diets for 30 days, rats were administered intravenous [¹⁴C]cholesterol and oral [³H]cholesterol. Analysis of the die-away curve of [¹⁴C]cholesterol showed an apparent independence of cholesterol kinetics to the dietary manipulations, but there was a moderate reduction of the size of the slowly exchangeable pool and of the biliary concentration of cholesterol when lysine was added to soybean protein. Addition of amino acids neither influenced cholesterol absorption nor the fecal excretion of the radioactivities from labeled cholesterol. The results indicate that manipulating the arginine/lysine ratio of dietary protein by adding single amino acids is not necessarily effective in ameliorating cholesterol metabolism in rats, although the arginine addition caused a significant reduction of serum cholesterol and triglyceride.     

NOTCH1, HIF1A and Other Cancer-Related Proteins in Lung Tissue from Uranium Miners—Variation by Occupational Exposure and Subtype of Lung Cancer

Background

Radon and arsenic are established pulmonary carcinogens. We investigated the association of cumulative exposure to these carcinogens with NOTCH1, HIF1A and other cancer-specific proteins in lung tissue from uranium miners.

Methodology/Principal Findings

Paraffin-embedded tissue of 147 miners was randomly selected from an autopsy repository by type of lung tissue, comprising adenocarcinoma (AdCa), squamous cell carcinoma (SqCC), small cell lung cancer (SCLC), and cancer-free tissue. Within each stratum, we additionally stratified by low or high level of exposure to radon or arsenic. Lifetime exposure to radon and arsenic was estimated using a quantitative job-exposure matrix developed for uranium mining. For 22 cancer-related proteins, immunohistochemical scores were calculated from the intensity and percentage of stained cells. We explored the associations of these scores with cumulative exposure to radon and arsenic with Spearman rank correlation coefficients (r_s). Occupational exposure was associated with an up-regulation of NOTCH1 (radon r_s = 0.18, 95% CI 0.02–0.33; arsenic: r_s = 0.23, 95% CI 0.07–0.38). Moreover, we investigated whether these cancer-related proteins can classify lung cancer using supervised and unsupervised classification. MUC1 classified lung cancer from cancer-free tissue with a failure rate of 2.1%. A two-protein signature discriminated SCLC (HIF1A low), AdCa (NKX2-1 high), and SqCC (NKX2-1 low) with a failure rate of 8.4%.

Conclusions/Significance

These results suggest that the radiation-sensitive protein NOTCH1 can be up-regulated in lung tissue from uranium miners by level of exposure to pulmonary carcinogens. We evaluated a three-protein signature consisting of a physiological protein (MUC1), a cancer-specific protein (HIF1A), and a lineage-specific protein (NKX2-1) that could discriminate lung cancer and its major subtypes with a low failure rate.     

Defective Lung Macrophage Function in Lung Cancer±Chronic Obstructive Pulmonary Disease (COPD/Emphysema)-Mediated by Cancer Cell Production of PGE2?

In chronic obstructive pulmonary disease (COPD/emphysema) we have shown a reduced ability of lung and alveolar (AM) macrophages to phagocytose apoptotic cells (defective ‘efferocytosis’), associated with evidence of secondary cellular necrosis and a resultant inflammatory response in the airway. It is unknown whether this defect is present in cancer (no COPD) and if so, whether this results from soluble mediators produced by cancer cells.We investigated efferocytosis in AM (26 controls, 15 healthy smokers, 37 COPD, 20 COPD+ non small cell lung cancer (NSCLC) and 8 patients with NSCLC without COPD) and tumor and tumor-free lung tissue macrophages (21 NSCLC with/13 without COPD). To investigate the effects of soluble mediators produced by lung cancer cells we then treated AM or U937 macrophages with cancer cell line supernatant and assessed their efferocytosis ability. We qualitatively identified Arachidonic Acid (AA) metabolites in cancer cells by LC-ESI-MSMS, and assessed the effects of COX inhibition (using indomethacin) on efferocytosis.Decreased efferocytosis was noted in all cancer/COPD groups in all compartments. Conditioned media from cancer cell cultures decreased the efferocytosis ability of both AM and U937 macrophages with the most pronounced effects occurring with supernatant from SCLC (an aggressive lung cancer type). AA metabolites identified in cancer cells included PGE2. The inhibitory effect of PGE2 on efferocytosis, and the involvement of the COX-2 pathway were shown.Efferocytosis is decreased in COPD/emphysema and lung cancer; the latter at least partially a result of inhibition by soluble mediators produced by cancer cells that include PGE2.     

Do Lung Cancer Eligibility Criteria Align with Risk among Blacks and Hispanics?

Background

Black patients have higher lung cancer risk despite lower pack years of smoking. We assessed lung cancer risk by race, ethnicity, and sex among a nationally representative population eligible for lung cancer screening based on Medicare criteria.

Methods

We used data from the National Health and Nutrition Examination Survey, 2007–2012 to assess lung cancer risk by sex, race and ethnicity among persons satisfying Medicare age and pack-year smoking eligibility criteria for lung cancer screening. We assessed Medicare eligibility based on age (55–77 years) and pack-years (≥30). We assessed 6-year lung cancer risk using a risk prediction model from Prostate, Lung, Colorectal and Ovarian Cancer Screening trial that was modified in 2012 (PLCO_m2012). We compared the proportions of eligible persons by sex, race and ethnicity using Medicare criteria with a risk cut-point that was adjusted to achieve comparable total number of persons eligible for screening.

Results

Among the 29.7 million persons aged 55–77 years who ever smoked, we found that 7.3 million (24.5%) were eligible for lung cancer screening under Medicare criteria. Among those eligible, Blacks had statistically significant higher (4.4%) and Hispanics lower lung cancer risk (1.2%) than non-Hispanic Whites (3.2%). At a cut-point of 2.12% risk for lung screening eligibility, the percentage of Blacks and Hispanics showed statistically significant changes. Blacks eligible rose by 48% and Hispanics eligible declined by 63%. Black men and Hispanic women were affected the most. There was little change in eligibility among Whites.

Conclusion

Medicare eligibility criteria for lung cancer screening do not align with estimated risk for lung cancer among Blacks and Hispanics. Data are urgently needed to determine whether use of risk-based eligibility screening improves lung cancer outcomes among minority patients.     

Viral Infection of Human Lung Macrophages Increases PDL1 Expression via IFNβ

Lung macrophages are an important defence against respiratory viral infection and recent work has demonstrated that influenza-induced macrophage PDL1 expression in the murine lung leads to rapid modulation of CD8+ T cell responses via the PD1 receptor. This PD1/PDL1 pathway may downregulate acute inflammatory responses to prevent tissue damage. The aim of this study was to investigate the mechanisms of PDL1 regulation by human macrophages in response to viral infection. Ex-vivo viral infection models using influenza and RSV were established in human lung explants, isolated lung macrophages and monocyte-derived macrophages (MDM) and analysed by flow cytometry and RT-PCR. Incubation of lung explants, lung macrophages and MDM with X31 resulted in mean cellular infection rates of 18%, 18% and 29% respectively. Viral infection significantly increased cell surface expression of PDL1 on explant macrophages, lung macrophages and MDM but not explant epithelial cells. Infected MDM induced IFNγ release from autologous CD8+ T cells, an effect enhanced by PDL1 blockade. We observed increases in PDL1 mRNA and IFNβ mRNA and protein release by MDM in response to influenza infection. Knockdown of IFNβ by siRNA, resulted in a 37.5% reduction in IFNβ gene expression in response to infection, and a significant decrease in PDL1 mRNA. Furthermore, when MDM were incubated with IFNβ, this cytokine caused increased expression of PDL1 mRNA. These data indicate that human macrophage PDL1 expression modulates CD8+ cell IFNγ release in response to virus and that this expression is regulated by autologous IFNβ production.