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Background: Advanced diagnostic bronchoscopy targeting the lung periphery has developed at an accelerated pace over the last two decades, whereas evidence to support introduction of innovative technologies has been variable and deficient. A major gap relates to variable reporting of diagnostic yield, in addition to limited comparative studies. Objectives: To develop a research framework to standardize the evaluation of advanced diagnostic bronchoscopy techniques for peripheral lung lesions. Specifically, we aimed for consensus on a robust definition of diagnostic yield, and we propose potential study designs at various stages of technology development. Methods: Panel members were selected for their diverse expertise. Workgroup meetings were conducted in virtual or hybrid format. The cochairs subsequently developed summary statements, with voting proceeding according to a modified Delphi process. The statement was cosponsored by the American Thoracic Society and the American College of Chest Physicians. Results: Consensus was reached on 15 statements on the definition of diagnostic outcomes and study designs. A strict definition of diagnostic yield should be used, and studies should be reported according to the STARD (Standards for Reporting Diagnostic Accuracy Studies) guidelines. Clinical or radiographic follow-up may be incorporated into the reference standard definition but should not be used to calculate diagnostic yield from the procedural encounter. Methodologically robust comparative studies, with incorporation of patient-reported outcomes, are needed to adequately assess and validate minimally invasive diagnostic technologies targeting the lung periphery. Conclusions: This American Thoracic Society/American College of Chest Physicians statement aims to provide a research framework that allows greater standardization of device validation efforts through clearly defined diagnostic outcomes and robust study designs. High-quality studies, both industry and publicly funded, can support subsequent health economic analyses and guide implementation decisions in various healthcare settings.
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Neoplasias Pulmonares , Médicos , Humanos , Neoplasias Pulmonares/diagnóstico , Consenso , Broncoscopia/métodos , Técnica Delphi , Pulmão/patologia , Assistência Centrada no PacienteRESUMO
RATIONALE: Despite significant advances in precision treatments and immunotherapy, lung cancer is the most common cause of cancer death worldwide. To reduce incidence and improve survival rates, a deeper understanding of lung premalignancy and the multistep process of tumorigenesis is essential, allowing for timely and effective intervention before cancer development. OBJECTIVES: To summarize existing information, identify knowledge gaps, formulate research questions, prioritize potential research topics, and propose strategies for future investigations into the premalignant progression in the lung. METHODS: An international multidisciplinary team of basic, translational, and clinical scientists reviewed available data to develop and refine research questions pertaining to the transformation of premalignant lung lesions to advanced lung cancer. RESULTS: This research statement identifies significant gaps in knowledge and proposes potential research questions aimed at expanding our understanding of the mechanisms underlying the progression of premalignant lung lesions to lung cancer in an effort to explore potential innovative modalities to intercept lung cancer at its nascent stages. CONCLUSIONS: The identified gaps in knowledge about the biological mechanisms of premalignant progression in the lung, along with ongoing challenges in screening, detection, and early intervention, highlight the critical need to prioritize research in this domain. Such focused investigations are essential to devise effective preventive strategies that may ultimately decrease lung cancer incidence and improve patient outcomes.
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DNA-dependent protein kinase (DNA-PK) plays a critical role in the non-homologous end joining (NHEJ) repair pathway and the DNA damage response (DDR). DNA-PK has therefore been pursued for the development of anti-cancer therapeutics in combination with ionizing radiation (IR). We report the discovery of a new class of DNA-PK inhibitors that act via a novel mechanism of action, inhibition of the Ku-DNA interaction. We have developed a series of highly potent and specific Ku-DNA binding inhibitors (Ku-DBi's) that block the Ku-DNA interaction and inhibit DNA-PK kinase activity. Ku-DBi's directly interact with the Ku and inhibit in vitro NHEJ, cellular NHEJ, and potentiate the cellular activity of radiomimetic agents and IR. Analysis of Ku-null cells demonstrates that Ku-DBi's cellular activity is a direct result of Ku inhibition, as Ku-null cells are insensitive to Ku-DBi's. The utility of Ku-DBi's was also revealed in a CRISPR gene-editing model where we demonstrate that the efficiency of gene insertion events was increased in cells pre-treated with Ku-DBi's, consistent with inhibition of NHEJ and activation of homologous recombination to facilitate gene insertion. These data demonstrate the discovery and application of new series of compounds that modulate DNA repair pathways via a unique mechanism of action.
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Reparo do DNA por Junção de Extremidades/efeitos dos fármacos , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Autoantígeno Ku/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Células Cultivadas , DNA/química , Quebras de DNA de Cadeia Dupla , Edição de Genes , Humanos , Autoantígeno Ku/química , Camundongos , Inibidores de Proteínas Quinases/químicaRESUMO
Defining detailed genomic characterization of early tumor progression is critical to identifying key regulators and pathways in carcinogenesis as potentially druggable targets. In human lung cancer, work to characterize early cancer development has mainly focused on squamous cancer, as the earliest lesions are more proximal in the airways and often accessible by repeated bronchoscopy. Adenocarcinomas are typically located distally in the lung, limiting accessibility for biopsy of pre-malignant and early stages. Mouse lung cancer models recapitulate many human genomic features and provide a model for tumorigenesis with pre-malignant atypical adenomatous hyperplasia and in situ adenocarcinomas often developing contemporaneously within the same animal. Here, we combined tissue characterization and collection by laser capture microscopy (LCM) with digital droplet PCR (ddPCR) and low-coverage whole genome sequencing (LC-WGS). ddPCR can be used to identify specific missense mutations in Kras (Kirsten rat sarcoma viral oncogene homolog, here focused on Kras Q61) and estimate the percentage of mutation predominance. LC-WGS is a cost-effective method to infer localized copy number alterations (CNAs) across the genome using low-input DNA. Combining these methods, the histological stage of lung cancer can be correlated with appearance of Kras mutations and CNAs. The utility of this approach is adaptable to other mouse models of human cancer.
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Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética , Lesões Pré-Cancerosas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenocarcinoma de Pulmão/induzido quimicamente , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Animais , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Feminino , Microdissecção e Captura a Laser/métodos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Reação em Cadeia da Polimerase/métodos , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Sequenciamento Completo do Genoma/métodosRESUMO
Rationale: Immune checkpoint inhibitors (ICIs) have revolutionized cancer care but are associated with unique adverse events, including potentially life-threatening pneumonitis. The diagnosis of ICI-pneumonitis is increasing; however, the biological mechanisms, clinical and radiologic features, and the diagnosis and management have not been well defined.Objectives: To summarize evidence, identify knowledge and research gaps, and prioritize topics and propose methods for future research on ICI-pneumonitis.Methods: A multidisciplinary group of international clinical researchers reviewed available data on ICI-pneumonitis to develop and refine research questions pertaining to ICI-pneumonitis.Results: This statement identifies gaps in knowledge and develops potential research questions to further expand knowledge regarding risk, biologic mechanisms, clinical and radiologic presentation, and management of ICI-pneumonitis.Conclusions: Gaps in knowledge of the basic biological mechanisms of ICI-pneumonitis, coupled with a precipitous increase in the use of ICIs alone or combined with other therapies, highlight the importance in triaging research priorities for ICI-pneumonitis.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Genes cdc/imunologia , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Pneumonia/induzido quimicamente , Pesquisa Biomédica , Humanos , Objetivos Organizacionais , Projetos de Pesquisa , Fatores de Risco , Sociedades Médicas , Estados UnidosRESUMO
Cigarette smoke (CS) contains hundreds of carcinogens and is a potent inducer of oxidative and bulky DNA damage, which when insufficiently repaired leads to activation of DNA damage response and possibly mutations. The DNA repair protein xeroderma pigmentosum group C (XPC) is primed to play an important role in CS-induced DNA damage because of its function in initiating repair of both bulky oxidative DNA damage. We hypothesized that loss of XPC function will increase susceptibility to developing CS- and carcinogen-induced lung cancer through impaired repair of oxidative DNA damage. Mice deficient in XPC (XPC-/-) exposed to chronic CS developed lung tumors whereas their wild-type littermates (XPC+/+) did not. XPC-/- mice treated with the CS-carcinogen urethane developed lung adenocarcinomas representing progressive stages of tumor development, with lung tumor number increased 17-fold compared with XPC+/+ mice. Mice heterozygous for XPC (XPC+/-) demonstrated a gene-dose effect, developing an intermediate number of lung tumors with urethane treatment. Treatment of XPC-/- mice with the carcinogen 3-methylcholanthrene followed by the proliferative agent butylated hydroxytoluene resulted in a 2-fold increase in lung adenocarcinoma development. Finally, tumor number decreased 7-fold in the lungs of XPC-/- mice by concurrent treatment with the antioxidant, N-acetylcysteine. Altogether, this supports a mechanism by which decreased XPC expression promotes lung adenocarcinoma development in response to CS-carcinogen exposure, due in part to impaired oxidative DNA damage repair.
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Adenocarcinoma/induzido quimicamente , Adenocarcinoma/prevenção & controle , Carcinógenos/toxicidade , Fumar Cigarros/efeitos adversos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/prevenção & controle , Xeroderma Pigmentoso/metabolismo , Adenocarcinoma/metabolismo , Animais , Dano ao DNA , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo , Uretana/toxicidadeRESUMO
Cigarette smoke (CS) exposure is a major risk factor for the development of emphysema, a common disease characterized by loss of cells comprising the lung parenchyma. The mechanisms of cell injury leading to emphysema are not completely understood but are thought to involve persistent cytotoxic or mutagenic DNA damage induced by CS. Using complementary cell culture and mouse models of CS exposure, we investigated the role of the DNA repair protein, xeroderma pigmentosum group C (XPC), on CS-induced DNA damage repair and emphysema. Expression of XPC was decreased in mouse lungs after chronic CS exposure and XPC knockdown in cultured human lung epithelial cells decreased their survival after CS exposure due to activation of the intrinsic apoptosis pathway. Similarly, cell autophagy and apoptosis were increased in XPC-deficient mouse lungs and were further increased by CS exposure. XPC deficiency was associated with structural and functional changes characteristic of emphysema, which were worsened by age, similar to levels observed with chronic CS exposure. Taken together, these findings suggest that repair of DNA damage by XPC plays an important and previously unrecognized role in the maintenance of alveolar structures. These findings support that loss of XPC, possibly due to chronic CS exposure, promotes emphysema development and further supports a link between DNA damage, impaired DNA repair, and development of emphysema.
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Dano ao DNA/genética , Reparo do DNA/genética , Enfisema Pulmonar/genética , Fumaça/efeitos adversos , Fumar/efeitos adversos , Xeroderma Pigmentoso/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Transformada , Feminino , Predisposição Genética para Doença/genética , Humanos , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tecido Parenquimatoso/patologia , Enfisema Pulmonar/patologiaRESUMO
Lung squamous cell carcinoma (LUSC) is the second leading cause of lung cancer. Although characterized by high DNA mutational burdens and genomic complexity, the role of DNA repair in LUSC development is poorly understood. We sought to better understand the role of the DNA repair protein Xeroderma Pigmentosum Group C (XPC) in LUSC development. XPC knock-out (KO), heterozygous, and wild-type (WT) mice were exposed topically to N-nitroso-tris-chloroethylurea (NTCU), and lungs were evaluated for histology and pre-malignant progression in a blinded fashion at various time-points from 8-24 weeks. High-grade dysplasia and LUSC were increased in XPC KO compared with XPC WT NTCU mice (56% vs. 34%), associated with a higher mean LUSC lung involvement (p < 0.05). N-acetylcysteine pre-treatment decreased bronchoalveolar inflammation but did not prevent LUSC development. Proliferation, measured as %Ki67+ cells, increased with NTCU treatment, in high-grade dysplasia and LUSC, and in XPC deficiency (p < 0.01, ANOVA). Finally, pre-LUSC dysplasia developed earlier and progressed to higher histologic classification sooner in XPC KO compared with WT mice. Overall, this supports the protective role of XPC in squamous dysplasia progression to LUSC. Mouse models of early LUSC development are limited; this may provide a valuable model to study mechanisms of LUSC development and progression.
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Background: Black race is associated with advanced stage at diagnosis and increased mortality in non-small cell lung cancer (NSCLC). Most studies focus on race alone, without accounting for social determinants of health (SDOH). We explored the hypothesis that racial disparities in stage at diagnosis and outcomes are associated with SDOH and influence treatment decisions by patients and providers. Methods: Patients with NSCLC newly diagnosed at Indiana University Simon Comprehensive Cancer Center (IUSCCC) from January 1, 2000 to May 31, 2015 were studied. Multivariable regression analyses were conducted to examine the impact of SDOH (race, gender, insurance status, and marital status) on diagnosis stage, time to treatment, receipt of and reasons for not receiving guideline concordant treatment, and 5-year overall survival (OS) based on Kaplan-Meier curves. Results: A total of 3,349 subjects were included in the study, 12.2% of Black race. Those diagnosed with advanced-stage NSCLC had a significantly higher odds of being male, uninsured, and Black. Five-year OS was lower in those of Black race, male, single, uninsured, Medicare/Medicaid insurance, and advanced stage. Adjusted for multiple variables, individuals with Medicare, Medicare/Medicaid, uninsured, widowed, and advanced stage at diagnosis, were associated with significantly lower OS time. Black, single, widowed, and uninsured individuals were less likely to receive stage appropriate treatment for advanced disease. Those uninsured [odds ratio (OR): 3.876, P<0.001], Medicaid insurance (OR: 3.039, P=0.0017), and of Black race (OR: 1.779, P=0.0377) were less likely to receive curative-intent surgery for early-stage NSCLC because it was not a recommended treatment. Conclusions: We found racial, gender, and socioeconomic disparities in NSCLC diagnosis stage, receipt of stage-appropriate treatment, and reasons for guideline discordance in receipt of curative intent surgery for early-stage NSCLC. While insurance type and marital status were associated with worse OS, race alone was not. This suggests racial differences in outcomes may not be associated with race alone, but rather worse SDOH disproportionately affecting Black individuals. Efforts to understand advanced diagnosis and reasons for failure to receive stage-appropriate treatment by vulnerable populations is needed to ensure equitable NSCLC care.
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The treatment for advanced stage non-small cell lung cancer (NSCLC) often includes platinum-based chemotherapy and IR. Cisplatin and IR combination therapy display schedule and dose-dependent synergy, the mechanism of which is not completely understood. In a series of in vitro and cell culture assays in a NSCLC model, we investigated both the downstream and direct treatment and damage effects of cisplatin on NHEJ catalyzed repair of a DNA DSB. The results demonstrate that extracts prepared from cisplatin-treated cells are fully capable of NHEJ catalyzed repair of a DSB using a non-cisplatin-damaged DNA substrate in vitro. Similarly, using two different host cell reactivation assays, treatment of cells prior to transfection of a linear, undamaged reporter plasmid revealed no reduction in NHEJ compared with untreated cells. In contrast, transfection of a linear GFP-reporter plasmid containing site-specific, cisplatin lesions 6-bp from the termini revealed a significant impairment in DSB repair of the cisplatin-damaged DNA substrates in the absence of cellular treatment with cisplatin. Together, these data demonstrate that impaired NHEJ in combined cisplatin-IR treated cells is likely the result of a direct effect of cisplatin-DNA lesions near a DSB and that the indirect cellular effects of cisplatin treatment are not significant contributors to the synergistic cytotoxicity observed with combination cisplatin-IR treatment.
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Cisplatino/farmacologia , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Linhagem Celular Tumoral , Citometria de Fluxo , Humanos , Microscopia de Fluorescência , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
Xeroderma pigmentosum complementation group C (XPC) is a DNA damage recognition protein essential for initiation of global-genomic nucleotide excision repair (GG-NER). Humans carrying germline mutations in the XPC gene exhibit strong susceptibility to skin cancer due to defective removal via GG-NER of genotoxic, solar UV-induced dipyrimidine photoproducts. However, XPC is increasingly recognized as important for protection against non-dermatologic cancers, not only through its role in GG-NER, but also by participating in other DNA repair pathways, in the DNA damage response and in transcriptional regulation. Additionally, XPC expression levels and polymorphisms likely impact development and may serve as predictive and therapeutic biomarkers in a number of these non-dermatologic cancers. Here we review the existing literature, focusing on the role of XPC in non-dermatologic cancer development, progression, and treatment response, and highlight possible future applications of XPC as a prognostic and therapeutic biomarker.
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DNA repair capacity (DRC) is the ability of a cell to repair DNA damage. Differential DRC plays an important role in human disease, including lung and other cancers. Measuring DRC could aid in translational disease research and in personalizing treatment. We developed and optimized a flow cytometry-based assay to measure individual DRC using GFP-expressing plasmids modified by ultraviolet (UV) light for nucleotide excision repair (NER) and restriction enzyme digestion to induce a blunt double-strand cut between promoter and GFP expression regions for nonhomologous end joining (NHEJ). Cryopreserved peripheral blood mononuclear cells (PBMCs) from healthy volunteers were used to measure DRC and optimize the assay. Pathway specificity of the NHEJ DRC assay was confirmed using Ku80-/- MEF cells, which showed a 6-fold reduction in NHEJ compared to Ku80+/+. Using a cell mixing assay, we show a linear correlation between NHEJ DRC and the expected concentration of Ku80. NHEJ DRC measurements in cryopreserved PBMCs are quantifiable with low interindividual and inter-assay variability, and a titratable decrease in NHEJ activity was observed in PBMCs treated with the DNA-PK inhibitor NU7441. Pathway specificity of the NER DRC assay was confirmed by a decrease in measured NER activity in human XPC deficient compared to XPC proficient fibroblasts, with a linear correlation measured between NER DRC and expected XPC concentration by cell mixing assay. NER DRC is quantifiable, reproducible, and titratable in PBMCs from healthy volunteers. We measured both NER and NHEJ DRC in PBMCs obtained from newly diagnosed, untreated lung cancer patients; measured DRC differed in these PBMCs compared to healthy volunteers. With further investigation, measurement of NER and NHEJ DNA repair capacity may be useful in personalizing disease risk and response to DNA damaging therapies and small molecular inhibitors of DNA repair pathways using readily available human PBMCs.
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Reparo do DNA , Leucócitos Mononucleares , DNA , Dano ao DNA , Humanos , Raios UltravioletaRESUMO
Although IL-9 has potent anti-tumor activity in adoptive cell transfer therapy, some models suggest that it can promote tumor growth. Here, we show that IL-9 signaling is associated with poor outcomes in patients with various forms of lung cancer, and is required for lung tumor growth in multiple mouse models. CD4+ T cell-derived IL-9 promotes the expansion of both CD11c+ and CD11c- interstitial macrophage populations in lung tumor models. Mechanistically, the IL-9/macrophage axis requires arginase 1 (Arg1) to mediate tumor growth. Indeed, adoptive transfer of Arg1+ but not Arg1- lung macrophages to Il9r-/- mice promotes tumor growth. Moreover, targeting IL-9 signaling using macrophage-specific nanoparticles restricts lung tumor growth in mice. Lastly, elevated expression of IL-9R and Arg1 in tumor lesions is associated with poor prognosis in lung cancer patients. Thus, our study suggests the IL-9/macrophage/Arg1 axis is a potential therapeutic target for lung cancer therapy.
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Interleucina-9 , Neoplasias Pulmonares , Macrófagos , Animais , Carcinogênese/metabolismo , Interleucina-9/genética , Interleucina-9/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Macrófagos Alveolares/metabolismo , CamundongosRESUMO
Hemophagocytic lymphohistiocytosis is a life-threatening hyperinflammatory disorder that is associated with high morbidity and mortality in the ICU. It has also been associated with acute liver failure. DESIGN: Retrospective observational study. SETTING: Tertiary-care medical ICU. PATIENTS: Thirty-one patients critically ill with hemophagocytic lymphohistiocytosis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We performed a comprehensive review of critically ill hemophagocytic lymphohistiocytosis patients admitted to a tertiary-care medical ICU from January 2012 to December 2018. Most patients presented with constitutional symptoms and elevated liver enzymes and thrombocytopenia were common upon hospital admission. ICU admission laboratory and clinical variables were used to calculate Acute Physiology and Chronic Health Evaluation II, hemophagocytic syndrome diagnostic score, and model for end-stage liver disease. Mean age of the cohort was 48.1 years, and 45% were male. The mortality rate was 65% at 28 days and 77% at 1 year. About 28-day survivors were younger, had lower mean Acute Physiology and Chronic Health Evaluation II score (16.5 vs 23.0; p = 0.004), and higher mean hemophagocytic syndrome diagnostic score (249.1 vs 226.0; p = 0.032) compared with nonsurvivors. Survivors were less likely to receive mechanical ventilation, renal replacement therapy, or vasopressor support and were more likely to receive chemotherapy for hemophagocytic lymphohistiocytosis. In this ICU cohort, 29% were diagnosed with acute liver failure, of whom only 22% developed acute liver failure early during their hospital stay. Acute liver failure was associated with a higher model for end-stage liver disease score upon hospital admission. Available histology in those that developed acute liver failure showed massive hepatic necrosis, or histiocytic or lymphocytic infiltrates. CONCLUSIONS: Patients admitted to the ICU with hemophagocytic lymphohistiocytosis have a high mortality. Those who survived had lower Acute Physiology and Chronic Health Evaluation scores, had higher hemophagocytic syndrome diagnostic scores, are more likely to receive hemophagocytic lymphohistiocytosis specific chemotherapy, and are less likely to have organ failure. Hemophagocytic lymphohistiocytosis can be associated with acute liver failure especially when model for end-stage liver disease score is elevated upon admission.
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Biomarkers that focus on lung cancer risk assessment, detection, prognosis, diagnosis, and personalized treatment are in various stages of development. This article provides an overview of lung cancer biomarker development, focusing on clinical utility and highlighting 2 unmet clinical needs: selection of high-risk patients for lung cancer screening and differentiation of early lung cancer from benign pulmonary nodules. The authors highlight biomarkers under development and those lung cancer screening and nodule management biomarkers post-clinical validation. Finally, trends in lung cancer biomarker development that may improve accuracy and accelerate implementation in practice are discussed.
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Biomarcadores/metabolismo , Detecção Precoce de Câncer/métodos , Neoplasias Pulmonares/diagnóstico , Feminino , Humanos , Masculino , PrognósticoRESUMO
Cigarette smoking is the leading cause of lung cancer and chronic obstructive pulmonary disease (COPD). Many of the detrimental effects of cigarette smoke have been attributed to the development of DNA damage, either directly from chemicals contained in cigarette smoke or as a product of cigarette smoke-induced inflammation and oxidative stress. In this review, we discuss the environmental, epidemiological, and physiological links between COPD and lung cancer and the likely role of DNA damage and repair in COPD and lung cancer development. We explore alterations in DNA damage repair by DNA repair proteins and pathways. We discuss emerging data supporting a key role for the DNA repair protein, xeroderma pigmentosum group C (XPC), in cigarette smoke-induced COPD and early lung cancer development. Understanding the interplay between cigarette smoke, DNA damage repair, COPD, and lung cancer may lead to prognostic tools and new, potentially targetable, pathways for lung cancer prevention and treatment.
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Fumar Cigarros/efeitos adversos , Dano ao DNA , Reparo do DNA , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Terapia de Alvo Molecular , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/terapia , Humanos , Inflamação , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/prevenção & controle , Estresse Oxidativo , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/prevenção & controleRESUMO
RATIONALE: Few data have been published regarding scoring tools for selection of postgraduate medical trainee candidates that have wide applicability. OBJECTIVES: The authors present a novel scoring tool developed to assist postgraduate programs in generating an institution-specific rank list derived from selected elements of the U.S. Electronic Residency Application System (ERAS) application. METHODS: The authors developed and validated an ERAS and interview day scoring tool at five pulmonary and critical care fellowship programs: the ERAS Application Scoring Tool-Interview Scoring Tool. This scoring tool was then tested for intrarater correlation versus subjective rankings of ERAS applications. The process for development of the tool was performed at four other institutions, and it was performed alongside and compared with the "traditional" ranking methods at the five programs and compared with the submitted National Residency Match Program rank list. RESULTS: The ERAS Application Scoring Tool correlated highly with subjective faculty rankings at the primary institution (average Spearman's r = 0.77). The ERAS Application Scoring Tool-Interview Scoring Tool method correlated well with traditional ranking methodology at all five institutions (Spearman's r = 0.54, 0.65, 0.72, 0.77, and 0.84). CONCLUSIONS: This study validates a process for selecting and weighting components of the ERAS application and interview day to create a customizable, institution-specific tool for ranking candidates to postgraduate medical education programs. This scoring system can be used in future studies to compare the outcomes of fellowship training.
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Bolsas de Estudo , Internato e Residência , Seleção de Pessoal , Pneumologia/educação , Humanos , Candidatura a Emprego , Estados UnidosRESUMO
Non-small cell lung cancers (NSCLC) are commonly treated with a platinum-based chemotherapy such as cisplatin (CDDP) in combination with ionizing radiation (IR). Although clinical trials have demonstrated that the combination of CDDP and IR appear to be synergistic in terms of therapeutic efficacy, the mechanism of synergism remains largely uncharacterized. We investigated the role of the DNA damage response (DDR) in CDDP radiosensitization using two NSCLC cell lines. Using clonogenic survival assays, we determined that the cooperative cytotoxicity of CDDP and IR treatment is sequence dependent, requiring administration of CDDP prior to IR (CDDP-IR). We identified and interrogated the unique time and agent-dependent activation of the DDR in NSCLC cells treated with cisplatin-IR combination therapy. Compared to treatment with CDDP or IR alone, CDDP-IR combination treatment led to persistence of γH2Ax foci, a marker of DNA double-strand breaks (DSB), for up to 24h after treatment. Interestingly, pharmacologic inhibition of DDR sensor kinases revealed the persistence of γ-H2Ax foci in CDDP-IR treated cells is independent of kinase activation. Taken together, our data suggest that delayed repair of DSBs in NSCLC cells treated with CDDP-IR contributes to CDDP radiosensitization and that alterations of the DDR pathways by inhibition of specific DDR kinases can augment CDDP-IR cytotoxicity by a complementary mechanism.