Browsing by Author "Sears, Catherine R."
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Item DNA damage response (DDR) pathway engagement in cisplatin radiosensitization of non-small cell lung cancer(Elsevier, 2016-04) Sears, Catherine R.; Cooney, Sean A.; Chin-Sinex, Helen; Mendonca, Marc S.; Turchi, John J.; Department of Medicine, School of MedicineNon-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.Item DNA Repair as an Emerging Target for COPD-Lung Cancer Overlap(Elsevier, 2019-03) Sears, Catherine R.; Medicine, School of MedicineCigarette 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.Item DNA Repair Capacity for Personalizing Risk and Treatment Response - Assay Development and Optimization in Human Peripheral Blood Mononuclear Cells (PBMCs)(Elsevier, 2022) Al Nasrallah, Nawar; Zhou, Huaxin; Smith, Patricia A.; Sears, Catherine R.; Medicine, School of MedicineDNA 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.Item DNA repair targeted therapy: The past or future of cancer treatment?(Elsevier, 2016-04) Gavande, Navnath S.; VanderVere-Carozza, Pamela S.; Hinshaw, Hilary D.; Jalal, Shadia I.; Sears, Catherine R.; Pawelczak, Katherine S.; Turchi, John J.; Department of Medicine, School of MedicineThe repair of DNA damage is a complex process that relies on particular pathways to remedy specific types of damage to DNA. The range of insults to DNA includes small, modest changes in structure including mismatched bases and simple methylation events to oxidized bases, intra- and interstrand DNA crosslinks, DNA double strand breaks and protein-DNA adducts. Pathways required for the repair of these lesions include mismatch repair, base excision repair, nucleotide excision repair, and the homology directed repair/Fanconi anemia pathway. Each of these pathways contributes to genetic stability, and mutations in genes encoding proteins involved in these pathways have been demonstrated to promote genetic instability and cancer. In fact, it has been suggested that all cancers display defects in DNA repair. It has also been demonstrated that the ability of cancer cells to repair therapeutically induced DNA damage impacts therapeutic efficacy. This has led to targeting DNA repair pathways and proteins to develop anti-cancer agents that will increase sensitivity to traditional chemotherapeutics. While initial studies languished and were plagued by a lack of specificity and a defined mechanism of action, more recent approaches to exploit synthetic lethal interaction and develop high affinity chemical inhibitors have proven considerably more effective. In this review we will highlight recent advances and discuss previous failures in targeting DNA repair to pave the way for future DNA repair targeted agents and their use in cancer therapy.Item Hemophagocytic Lymphohistiocytosis in the Medical ICU: A Single-Institution Cohort Study on Acute Liver Failure and Mortality(Wolters Kluwer, 2021-01-08) Al Nasrallah, Nawar; Al-Hader, Ahmad; Samala, Niharika; Sears, Catherine R.; Medicine, School of MedicineHemophagocytic 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.Item Knowledge Gaps and Research Priorities in Immune Checkpoint Inhibitor–related Pneumonitis. An Official American Thoracic Society Research Statement(American Thoracic Society - AJRCCM, 2019-09-15) Sears, Catherine R.; Peikert, Tobias; Possick, Jennifer D.; Naidoo, Jarushka; Nishino, Mizuki; Patel, Sandip P.; Camus, Philippe; Gaga, Mina; Garon, Edward B.; Gould, Michael K.; Limper, Andrew H.; Montgrain, Philippe R.; Travis, William D.; Rivera, M. Patricia; Medicine, School of MedicineRationale: 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.Item Low-Coverage Whole Genome Sequencing Using Laser Capture Microscopy with Combined Digital Droplet PCR: An Effective Tool to Study Copy Number and Kras Mutations in Early Lung Adenocarcinoma Development(MDPI, 2021-11-06) Mickler, Elizabeth A.; Zhou, Huaxin; Phang, Tzu L.; Geraci, Mark W.; Stearman, Robert S.; Sears, Catherine R.; Medicine, School of MedicineDefining 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.Item Mortality Rates in a Diverse Cohort of Mechanically Ventilated Patients With Novel Coronavirus in the Urban Midwest(Wolters Kluwer, 2020-08) Twigg, Homer L. III; Khan, Sikandar H.; Perkins, Anthony J.; Roberts, Scott; Sears, Catherine R.; Rahman, Omar; Smith, Joseph P.; Kapoor, Rajat; Farber, Mark O.; Ellender, Timothy; Carlos, Graham; Gilroy, Grant; Buckley, John; Bosslet, Gabriel; Machado, Roberto; Gao, Sujuan; Khan, Babar A.; Medicine, School of MedicineObjectives: Differences in mortality rates previously reported in critically ill patients with coronavirus disease 2019 have increased the need for additional data on mortality and risk factors for death. We conducted this study to describe length of stay, mortality, and risk factors associated with in-hospital mortality in mechanically ventilated patients with coronavirus disease 2019. Design: Observational study. Setting: Two urban, academic referral hospitals in Indianapolis, Indiana. Patients or Subjects: Participants were critically ill patients 18 years old and older, admitted with coronavirus disease 2019 between March 1, 2020, and April 27, 2020. Interventions: None. Measurements and Main Results: Outcomes included in-hospital mortality, duration of mechanical ventilation, and length of stay. A total of 242 patients were included with mean age of 59.6 years (sd, 15.5 yr), 41.7% female and 45% African American. Mortality in the overall cohort was 19.8% and 20.5% in the mechanically ventilated subset. Patients who died were older compared with those that survived (deceased: mean age, 72.8 yr [sd, 10.6 yr] vs patients discharged alive: 54.3 yr [sd, 14.8 yr]; p < 0.001 vs still hospitalized: 59.5 yr [sd, 14.4 yr]; p < 0.001) and had more comorbidities compared with those that survived (deceased: 2 [0.5–3] vs survived: 1 [interquartile range, 0–1]; p = 0.001 vs still hospitalized: 1 [interquartile range, 0–2]; p = 0.015). Older age and end-stage renal disease were associated with increased hazard of in-hospital mortality: age 65–74 years (hazard ratio, 3.1 yr; 95% CI, 1.2–7.9 yr), age 75+ (hazard ratio, 4.1 yr; 95% CI, 1.6–10.5 yr), and end-stage renal disease (hazard ratio, 5.9 yr; 95% CI, 1.3–26.9 yr). The overall median duration of mechanical ventilation was 9.3 days (interquartile range, 5.7–13.7 d), and median ICU length of stay in those that died was 8.7 days (interquartile range, 4.0–14.9 d), compared with 9.2 days (interquartile range, 4.0–14.0 d) in those discharged alive, and 12.7 days (interquartile range, 7.2–20.3 d) in those still remaining hospitalized. Conclusions: We found mortality rates in mechanically ventilated patients with coronavirus disease 2019 to be lower than some previously reported with longer lengths of stay.Item Mouse pulmonary interstitial macrophages mediate the pro-tumorigenic effects of IL-9(Springer Nature, 2022-07-01) Fu, Yongyao; Pajulas, Abigail; Wang, Jocelyn; Zhou, Baohua; Cannon, Anthony; Cheung, Cherry Cheuk Lam; Zhang, Jilu; Zhou, Huaxin; Fisher, Amanda Jo; Omstead, David T.; Khan, Sabrina; Han, Lei; Renauld, Jean-Christophe; Paczesny, Sophie; Gao, Hongyu; Liu, Yunlong; Yang, Lei; Tighe, Robert M.; Licona-Limón, Paula; Flavell, Richard A.; Takatsuka, Shogo; Kitamura, Daisuke; Sun, Jie; Bilgicer, Basar; Sears, Catherine R.; Yang, Kai; Kaplan, Mark H.; Microbiology and Immunology, School of MedicineAlthough 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.Item Racial disparities in staging, treatment, and mortality in non-small cell lung cancer(AME, 2024) Duncan, Francesca C.; Al Nasrallah, Nawar; Nephew, Lauren; Han, Yan; Killion, Andrew; Liu, Hao; Al-Hader, Ahmad; Sears, Catherine R.; Medicine, School of MedicineBackground: 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.