Interleukin-1 Receptor Antagonist Gene (IL1RN) Variants Modulate the Cytokine Release Syndrome and Mortality of COVID-19.

BACKGROUND: We examined effects of single-nucleotide variants (SNVs) of IL1RN, the gene encoding the anti-inflammatory interleukin 1 receptor antagonist (IL-1Ra), on the cytokine release syndrome (CRS) and mortality in patients with acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: IL1RN CTA haplotypes formed from 3 SNVs (rs419598, rs315952, rs9005) and the individual SNVs were assessed for association with laboratory markers of inflammation and mortality. We studied 2589 patients hospitalized with SARS-CoV-2 between March 2020 and March 2021. RESULTS: Mortality was 15.3% and lower in women than men (13.1% vs 17.3%, P = .0003). Carriers of the CTA-1/2 IL1RN haplotypes exhibited decreased inflammatory markers and increased plasma IL-1Ra. Evaluation of the individual SNVs of the IL1RN, carriers of the rs419598 C/C SNV exhibited significantly reduced inflammatory biomarker levels and numerically lower mortality compared to the C/T-T/T genotype (10.0% vs 17.8%, P = .052) in men, with the most pronounced association observed in male patients ≤74 years old, whose mortality was reduced by 80% (3.1% vs 14.0%, P = .030). CONCLUSIONS: The IL1RN haplotype CTA and C/C variant of rs419598 are associated with attenuation of the CRS and decreased mortality in men with acute SARS-CoV-2 infection. The data suggest that the IL1RN pathway modulates the severity of coronavirus disease 2019 (COVID-19) via endogenous anti-inflammatory mechanisms.

The association between food insecurity and colorectal cancer screening: 2018-2021 New York State Behavioral Risk Factor Surveillance System (BRFSS).

PURPOSE: To assess the association between food insecurity and colorectal cancer screening uptake in screening eligible participants in New York State. METHODS: We analyzed 28,154 adults who participated in New York State Behavioral Risk Factor Surveillance System (BRFSS) from 2018 to 2021, were age-eligible for colorectal cancer screening based on the USPSTF guidelines at the time of survey administration and answered a version of the administered survey that included the module on food insecurity. Participants were defined as food insecure if they self-reported being always, usually, or sometimes stressed about having enough money to buy nutritious meals in the past 12 months. We compared demographic, healthcare access, overall health status, food insecurity by colorectal cancer screening status. Multivariable analyses were performed to assess the association of food insecurity and colorectal cancer screening status after adjusting for relevant covariates. Weighted analyses were performed using survey procedures to obtain population estimates. RESULTS: Food insecurity was statistically significantly associated a decreased likelihood of being up to date on colorectal cancer screening (ORadj 0.83, 95% CI [0.72, 0.94]) and being ever screened for colorectal cancer (ORadj 0.74, 95% CI [0.64, 0.87]) after adjusting for overall health status, healthcare coverage, interview year, age, race/ethnicity, sex, educational attainment, and income. Health status, health coverage, age, and Non-Hispanic Black race/ethnicity showed positive, statistically significant association with ever being screened and with being up to date for colorectal cancer screening. Lower income, lower educational attainment, and non-Hispanic Asian race/ethnicity were statistically significant inverse predictors of ever being screened and being up to date on screening. CONCLUSION: This project assessed the association between food insecurity and colorectal cancer screening uptake using the BRFSS survey. Food insecurity may be an important predictor for colorectal cancer screening uptake in eligible adults in the United States. The results from the study can inform future interventions and policies designed to improve participation in routine colorectal cancer screening.

Patients With Surgically Resectable Lung Cancer Who Opt for Radiation Have Worse Outcomes.

BACKGROUND: Surgery has been the standard procedure for resectable primary LC. Survival after stereotactic body radiation therapy, another treatment, is significantly biased due to preponderance of data from patients deemed unsuitable for surgery. We examined survival of patients refusing surgery in favor of radiation therapy. METHODS: We used the Surveillance, Epidemiology, and End Results database to identify patients with primary Stage I NSCLC diagnosed between 2007 and 2016. Patients were excluded if it was unknown if they were recommended for surgery or if surgery was contraindicated. Multiple predictors were assessed: radiation versus surgery, age at diagnosis, sex, race/ethnicity, health insurance status, marital status, tumor size, and histology. A multivariate analysis was performed to estimate hazard ratios and generate Kaplan-Meier survival curves. RESULTS: When adjusted for confounding variables, survival was greater for patients undergoing surgical resection than those refusing surgery in favor of radiation (HRadj 2.66; 95% CI: 2.27-3.11, p < 0.001) or for those receiving no standardized treatment (HRadj 4.43; 95% CI: 3.57-5.50, p < 0.001). CONCLUSIONS: SBRT is an effective treatment for inoperable early LC but there is limited data comparing outcomes against surgical resection. When eligible for both, patients refusing surgery and choosing radiation had worse survival when adjusting for variables including age, tumor size, and histology, and suggests that surgical resection is a superior treatment modality.

Global DNA methylation of WTC prostate cancer tissues show signature differences compared to non-exposed cases.

There is increased incidence of prostate cancer (PC) among World Trade Center (WTC)-exposed responders and community members, with preliminary evidence suggestive of more aggressive disease. While previous research is supportive of differences in DNA methylation and gene expression as a consequence of WTC exposure, as measured in blood of healthy individuals, the epigenetics of WTC PC tissues has yet to be explored. Patients were recruited from the World Trade Center Health Program. Non-WTC PC samples were frequency matched on age, race/ethnicity and Gleason score. Bisulfite-treated DNA was extracted from tumor tissue blocks and used to assess global DNA methylation with the MethylationEPIC BeadChip. Differential and pathway enrichment analyses were conducted. RNA from the same tumor blocks was used for gene expression analysis to further support DNA methylation findings. Methylation data were generated for 28 samples (13 WTC and 15 non-WTC). Statistically significant differences in methylation were observed for 3,586 genes; on average WTC samples were statistically significantly more hypermethylated (P = 0.04131). Pathway enrichment analysis revealed hypermethylation in epithelial mesenchymal transition (EMT), hypoxia, mitotic spindle, TNFA signaling via NFKB, WNT signaling, and TGF beta signaling pathways in WTC compared to non-WTC samples. The androgen response, G2M and MYC target pathways were hypomethylated. These results correlated well with RNA gene expression. In conclusion, long-term epigenic changes associated with WTC dust exposure were observed in PC tissues. These occurred in genes of critical pathways, likely increasing prostate tumorigenesis potential. This warrants analysis of larger WTC groups and other cancer types.

Modulation of chemoimmunotherapy efficacy in non-small cell lung cancer by sex and histology: a real-world, patient-level analysis.

BACKGROUND: It has been postulated that patient's sex impacts response to immunotherapy. Sex modulation of immunotherapy benefit, however, has not yet been explored using patient-level data, where potential confounders, as well as histologic type, can be accounted for. Here we investigated the association between sex and chemoimmunotherapy efficacy for non-small cell lung cancer (NSCLC) using a large, nation-wide dataset. PATIENTS & METHODS: Stage IV NSCLC patients diagnosed in 2015 were identified in the National Cancer Database (NCDB). Patients were treated with either chemoimmunotherapy or chemotherapy alone. The efficacy of the addition of immunotherapy treatment by sex was investigated using both an adjusted Cox proportional hazards model and propensity-score matching, in both the overall cohort and stratified by histological subtype. RESULTS: 2064 (16%) patients received chemoimmunotherapy and10,733 (84%) received chemotherapy alone. Adjusted survival analysis in the overall cohort showed that both males (hazards ratio (HR)adj: 0.80, 95% CI: 0.74-0.87) and females (HRadj: 0.83, 95% CI: 0.76-0.90) had better OS when treated with chemoimmunotherapy than chemotherapy alone, with no statistically significant interaction between sex and receipt of immunotherapy (p = 0.63). Propensity matching confirmed these results. However, for those with squamous cell histology, male patients derived more benefit from chemoimmunotherapy treatment than females (HRadj: 0.73, 95% CI: 0.58-0.91 vs HRadj: 1.03, 95% CI: 0.76-1.38; p for interaction = 0.07). CONCLUSION: Male patients with squamous cell carcinoma may derive more benefit from chemoimmunotherapy treatment. Histology likely plays an important role in how sex modulates immunotherapy efficacy.

Disparities in surgery for early-stage cancer: the impact of refusal.

BACKGROUND: For early-stage cancer surgery is often curative, yet refusal of recommended surgical interventions may be contributing to disparities in patient treatment. This study aims to assess predictors of early-stage cancers surgery refusal, and the impact on survival. METHODS: Patients recommended surgery with primary stage I and II lung, prostate, breast, and colon cancers, diagnosed between 2007-2014, were identified in the Surveillance, Epidemiology and End Results database (n = 498,927). Surgery refusal was reported for 5,757 (1.2%) patients. Associations between sociodemographic variables and surgery refusal by cancer type were assessed in adjusted multivariable logistic regression models. The impact of refusal on survival was investigated using adjusted Cox-Proportional Hazard regression in a propensity score-matched cohort. RESULTS: Increasing age (p < 0.0001 for all four cancer types), non-Hispanic Black race/ethnicity (ORadjBREAST 2.00, 95% CI 1.68-2.39; ORadjCOLON 3.04, 95% CI 2.17-4.26; ORadjLUNG 2.19, 95% CI 1.77-2.71; ORadjPROSTATE 2.02, 95% CI 1.86-2.20; vs non-Hispanic White), insurance status (uninsured: ORadjBREAST 2.75, 95% CI 1.89-3.99; ORadjPROSTATE 2.10, 95% CI 1.72-2.56; vs insured), marital status (ORadjBREAST 2.16, 95% CI 1.85-2.51; ORadjCOLON 1.56, 95% CI 1.16-2.10; ORadjLUNG 2.11, 95% CI 1.80-2.47; ORadjPROSTATE 1.94, 95% CI 1.81-2.09), and stage (ORadjBREAST 1.94, 95% CI 1.70-2.22; ORadjCOLON 0.13, 95% CI 0.09-0.18; ORadjLUNG 0.71, 95% CI 0.52-0.96) were all associated with refusal; patients refusing surgery were at increased risk of death compared to patients who underwent surgery. CONCLUSIONS: More vulnerable patients are at higher risk of refusing recommended surgery, and this decision negatively impacts their survival.

Complementary biobank of rodent tissue samples to study the effect of World Trade Center exposure on cancer development.

World Trade Center (WTC) responders were exposed to mixture of dust, smoke, chemicals and carcinogens. New York University (NYU) and Mount Sinai have recreated WTC exposure in rodents to observe the resulting systemic and local biological responses. These experiments aid in the interpretation of epidemiological observations and are useful for understanding the carcinogenesis process in the exposed human WTC cohort. Here we describe the implementation of a tissue bank system for the rodents experimentally exposed to WTC dust. NYU samples were experimentally exposed to WTC dust via intratracheal inhalation that mimicked conditions in the immediate aftermath of the disaster. Tissue from Mount Sinai was derived from genetically modified mice exposed to WTC dust via nasal instillation. All processed tissues include annotations of the experimental design, WTC dust concentration/dose, exposure route and duration, genetic background of the rodent, and method of tissue isolation/storage. A biobank of tissue from rodents exposed to WTC dust has been compiled representing an important resource for the scientific community. The biobank remains available as a scientific resource for future research through established mechanisms for samples request and utilization. Studies using the WTC tissue bank would benefit from confirming their findings in corresponding tissues from organs of animals experimentally exposed to WTC dust. Studies on rodent tissues will advance the understanding of the biology of the tumors developed by WTC responders and ultimately impact the modalities of treatment, and the probability of success and survival of WTC cancer patients.

The development of a Biobank of cancer tissue samples from World Trade Center responders.

BACKGROUND: World Trade Center (WTC) responders were exposed to mixture of dust, smoke, chemicals and carcinogens. Studies of cancer incidence in this population have reported elevated risks of cancer compared to the general population. There is a need to supplement current epidemiologic cancer follow-up with a cancer tissue bank in order to better elucidate a possible connection between each cancer and past WTC exposure. This work describes the implementation of a tissue bank system for the WTC newly diagnosed cancers, focused on advancing the understanding of the biology of these tumors. This will ultimately impact the modalities of treatment, and the probability of success and survival of these patients. METHODS: WTC Responders who participated (as employees or volunteers) in the rescue, recovery and cleanup efforts at the WTC sites have been enrolled at Mount Sinai in the World Trade Center Health Program. Responders with cancer identified and validated through linkages with New York, New Jersey, Pennsylvania, and Connecticut cancer registries were eligible to participate in this biobank. Potential participants were contacted through letters, phone calls, and emails to explain the research study, consent process, and to obtain the location where their cancer procedure was performed. Pathology departments were contacted to identify and request tissue samples. RESULTS: All the 866 solid cancer cases confirmed by the Data Center at Mount Sinai have been contacted and consent was requested for retrieval and storage of the tissue samples from their cancer. Hospitals and doctors' offices were then contacted to locate and identify the correct tissue block for each patient. The majority of these cases consist of archival paraffin blocks from surgical patients treated from 2002 to 2015. At the time of manuscript writing, this resulted in 280 cancer samples stored in the biobank. CONCLUSIONS: A biobank of cancer tissue from WTC responders has been compiled with 280 specimens in storage to date. This tissue bank represents an important resource for the scientific community allowing for high impact studies on environmental exposures and cancer etiology, cancer outcome, and gene-environment interaction in the unique population of WTC responders.

DNA Methylation as a Molecular Mechanism of Carcinogenesis in World Trade Center Dust Exposure: Insights from a Structured Literature Review.

The collapse of the World Trade Center (WTC) buildings in New York City generated a large plume of dust and smoke. WTC dust contained human carcinogens including metals, asbestos, polycyclic aromatic hydrocarbons (PAHs), persistent organic pollutants (POPs, including polychlorinated biphenyls (PCBs) and dioxins), and benzene. Excess levels of many of these carcinogens have been detected in biological samples of WTC-exposed persons, for whom cancer risk is elevated. As confirmed in this structured literature review (n studies = 80), all carcinogens present in the settled WTC dust (metals, asbestos, benzene, PAHs, POPs) have previously been shown to be associated with DNA methylation dysregulation of key cancer-related genes and pathways. DNA methylation is, therefore, a likely molecular mechanism through which WTC exposures may influence the process of carcinogenesis.

Racial and socioeconomic disparities in NSCLC molecular diagnostics uptake.

BACKGROUND: Precision therapies, such as targeted and immunotherapies, have substantially changed the landscape of late-stage non-small cell lung cancer (NSCLC). Yet utilization of these therapies is disproportionate across strata defined by race and socioeconomic status (SES), possibly due to disparities in molecular diagnostic testing (or "biomarker testing"), which is a prerequisite to treatment. METHODS: We extracted a cohort of NSCLC patients from the Surveillance, Epidemiology and End Results (SEER)-Medicare linked data. The primary outcome was receipt of a molecular diagnostic test, based on claims data. The primary predictors were race and SES. Likelihood of receiving a molecular diagnostic test, and overall survival (OS), were investigated using logistic and Cox proportional hazards regression, adjusted for sex, age, residence, histology, marital status, and comorbidity. RESULTS: Of the 28,511 NSCLC patients, 11,209 (39.3%) received molecular diagnostic testing. Compared to White patients, fewer Black patients received a molecular diagnostic test (40.4% vs 27.9%; p < .001). After adjustment, Black patients (ORadj [odds ratio]: 0.64; 95% CI [confidence interval]: 0.58-0.71) and those living in areas with greater poverty (ORadj: 0.85; 95% CI: 0.80-0.89) had statistically significant decreased likelihood of molecular diagnostic testing. Patients who did receive testing had a statistically significant decreased risk of death (HRadj [hazards ratio]: 0.74; 95% CI: 0.72-0.76). These results held in the stratified analysis of stage IV NSCLC patients. CONCLUSION: Disparities exist in comprehensive molecular diagnostics, which is critical for clinical decision making. Addressing barriers to molecular testing could help close gaps in cancer care and improve patient outcomes.

Genome-wide DNA methylation profiles and breast cancer among World Trade Center survivors.

Background: Increased incidence of cancer has been reported among World Trade Center (WTC)-exposed persons. Aberrant DNA methylation is a hallmark of cancer development. To date, only a few small studies have investigated the relationship between WTC exposure and DNA methylation. The main objective of this study was to assess the DNA methylation profiles of WTC-exposed community members who remained cancer free and those who developed breast cancer. Methods: WTC-exposed women were selected from the WTC Environmental Health Center clinic, with peripheral blood collected during routine clinical monitoring visits. The reference group was selected from the NYU Women's Health Study, a prospective cohort study with blood samples collected before 9 November 2001. The Infinium MethylationEPIC array was used for global DNA methylation profiling, with adjustments for cell type composition and other confounders. Annotated probes were used for biological pathway and network analysis. Results: A total of 64 WTC-exposed (32 cancer free and 32 with breast cancer) and 32 WTC-unexposed (16 cancer free and 16 with prediagnostic breast cancer) participants were included. Hypermethylated cytosine-phosphate-guanine probe sites (defined as ß > 0.8) were more common among WTC-exposed versus unexposed participants (14.3% vs. 4.5%, respectively, among the top 5000 cytosine-phosphate-guanine sites). Cancer-related pathways (e.g., human papillomavirus infection, cGMP-PKG) were overrepresented in WTC-exposed groups (breast cancer patients and cancer-free subjects). Compared to the unexposed breast cancer patients, 47 epigenetically dysregulated genes were identified among WTC-exposed breast cancers. These genes formed a network, including Wnt/ß-catenin signaling genes WNT4 and TCF7L2, and dysregulation of these genes contributes to cancer immune evasion. Conclusion: WTC exposure likely impacts DNA methylation and may predispose exposed individuals toward cancer development, possibly through an immune-mediated mechanism.

Personal and clinical characteristics associated with immunotherapy effectiveness in stage IV non-small cell lung cancer.

Background: Immunotherapy response rates in metastatic non-small cell lung cancer (NSCLC) are low and survival varies significantly. Factors like age, sex, race, and histology may modulate immunotherapy response. Existing analyses are limited to clinical trials, with limited generalizability, and meta-analyses where adjustment for potential confounders cannot be performed. Here, we conduct a cohort study with patient-level analysis to explore how personal and clinical characteristics moderate chemoimmunotherapy effectiveness in metastatic NSCLC. Methods: Stage IV NSCLC patients diagnosed in 2015 were drawn from Surveillance Epidemiology, and End Results-Medicare linked data. Receipt of chemoimmunotherapy and overall survival (OS) were the primary predictor and outcome of interest respectively. Multivariable Cox-proportional hazards regression and propensity-score matching were performed to evaluate the effectiveness of immunotherapy addition to chemotherapy. Results: From a total of 1,471 patients, 349 (24%) received chemoimmunotherapy and 1,122 (76%) received chemotherapy alone. Survival was significantly better among those treated with chemoimmunotherapy compared to those receiving chemotherapy alone [adjusted hazard ratio (HRadj) =0.72, 95% confidence interval (CI): 0.63-0.83]. Males saw significantly better OS from chemoimmunotherapy (HRadj =0.62, 95% CI: 0.51-0.75) than females (HRadj =0.81, 95% CI: 0.65-1.01, Pinteraction=0.0557). After propensity-score matching, the effect of chemoimmunotherapy was borderline significant according to sex (Pinteraction =0.0414), but not age or histology. Conclusions: Males may benefit more from chemoimmunotherapy, but there is limited evidence suggesting age, histology, race, and comorbidities contribute to differences in effectiveness. Future research should elucidate who responds best to chemoimmunotherapy, and further analyses of characteristics like race can inform how to tailor different treatment regimens to distinct patient subpopulations.

Antibiotic treatment and survival in non-small cell lung cancer patients receiving immunotherapy: a systematic review and meta-analysis.

Background: In patients with non-small cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs) are an effective mode of treatment. Despite their efficacy, responses to ICIs have been shown to differ based on several factors; for example, antibiotic use prior to and/or during immunotherapy has been associated with lower survival in NSCLC patients. The objective of this study is to provide an updated review of the literature and to fill in important knowledge gaps by accounting for potential confounding in the relationship between ICIs and survival. Methods: We performed a systematic review and meta-analysis on peer-reviewed studies that examined the effects of antibiotic use on overall survival (OS) and progression-free survival (PFS) in NSCLC patients treated with ICIs. We searched MEDLINE for studies published up to June 30th, 2023 that included NSCLC patients treated with anti-programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) agents, who received antibiotics before and/or during immunotherapy, and included a control group who did not receive antibiotics and had available data on the associations between antibiotics and OS and PFS. We calculated aggregated crude OS and PFS for all studies, and only for studies that reported multivariable hazard ratios (HRs). Risk of bias was assessed using a funnel plot. All results were synthesized and displayed using the metaphor statistical package in R, version 4.2.1. Results: Nineteen studies, conducted between 2017 and 2022, met the inclusion criteria, and included 2,932 patients with advanced and/or metastatic NSCLC. Compared to those who did not receive antibiotics, immunotherapy patients who did had a significantly reduced PFS (HR: 1.22, 95% CI: 1.03-1.44) and OS (HR: 1.56, 95% CI: 1.23-1.99). Adjusted HRs were even more pronounced (OS HRadj: 1.67, 95% CI: 1.23-2.27, PFS HRadj: 1.64, 95% CI: 1.16-2.32). Conclusions: NSCLC patients treated with antibiotics have significantly lowered survival compared with patients not treated with antibiotics. These results support the hypothesis that antibiotic use in conjunction with ICI among NSCLC patients lowers survival. Limitations of this analysis include the use of studies available only on a single database, limiting the literature search to NSCLC patients, which may impact the generalizability of results to other cancer patient populations, and the inability to account for and adjust the estimates for the same variables (e.g., age, sex) across all studies. Nevertheless, our findings underscore the importance of taking antibiotic use into consideration when using ICIs to treat NSCLC and suggest that confounders should be taken into account when designing future similar studies.

Interleukin-1 receptor antagonist gene ( IL1RN ) variants modulate the cytokine release syndrome and mortality of SARS-CoV-2.

Objective: To explore the regulation of the inflammatory response in acute SARS-CoV-2 infection, we examined effects of single nucleotide variants (SNVs) of IL1RN , the gene encoding the anti-inflammatory IL-1 receptor antagonist (IL-1Ra), on the cytokine release syndrome and mortality. Methods: We studied 2589 patients hospitalized with SARS-CoV-2 between March 2020 and March 2021 at NYU Langone's Tisch Hospital. CTA and TTG haplotypes formed from three SNVs (rs419598, rs315952, rs9005) and the individual SNVs of the IL1RN gene were assessed for association with laboratory markers of the cytokine release syndrome (CRS) and mortality. Results: Mortality in the population was 15.3%, and was lower in women than men (13.1% vs.17.3%, p<0.0003). Carriers of the CTA-1/2 IL1RN haplotypes exhibited decreased inflammatory markers and increased plasma IL-1Ra relative to TTG carriers. Decreased mortality among CTA-1/2 carriers was observed in male patients between the ages of 55-74 [9.2% vs. 17.9%, p=0.001]. Evaluation of individual SNVs of the IL1RN gene (rs419598, rs315952, rs9005) indicated that carriers of the IL1RN rs419598 CC SNV exhibited lower inflammatory biomarker levels, and was associated with reduced mortality compared to the CT/TT genotype in men (OR 0.49 (0.23 - 1.00); 0.052), with the most pronounced effect observed between the ages of 55-74 [5.5% vs. 18.4%, p<0.001]. Conclusion: The IL1RN haplotype CTA, and sequence variant of rs419598 are associated with attenuation of the cytokine release syndrome and decreased mortality in males with acute SARS-CoV2 infection. The data suggest that IL1RN modulates the COVID-19 cytokine release syndrome via endogenous " anti-inflammatory" mechanisms. Significance statement: We provide evidence that variants of IL1RN modulate the severity of SARS-CoV-2 infection. The IL1RN CTA haplotype and rs419598 CC single nucleotide variant are associated with decreased plasma levels of inflammatory markers, interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), interleukin-2 (IL-2), C-reactive protein (CRP), D-dimer, ferritin, and procalcitonin, in association with higher levels of IL-1Ra and IL-10, anti-inflammatory proteins. Both haplotype CTA and rs419598 CC genotype are associated with a significant reduction in the mortality of men. These data provide genetic evidence that inflammasome activation and the IL-1 pathway plays an important role in the mortality and morbidity associated with severe SARS-CoV-2 infection, and that genetic regulation of inflammatory pathways by variants of IL1RN merits further evaluation in severe SARS-CoV-2 infection.

World Trade Center Exposure, DNA Methylation Changes, and Cancer: A Review of Current Evidence.

Introduction: Known carcinogens in the dust and fumes from the destruction of the World Trade Center (WTC) towers on 9 November 2001 included metals, asbestos, and organic pollutants, which have been shown to modify epigenetic status. Epigenome-wide association analyses (EWAS) using uniform (Illumina) methodology have identified novel epigenetic profiles of WTC exposure. Methods: We reviewed all published data, comparing differentially methylated gene profiles identified in the prior EWAS studies of WTC exposure. This included DNA methylation changes in blood-derived DNA from cases of cancer-free "Survivors" and those with breast cancer, as well as tissue-derived DNA from "Responders" with prostate cancer. Emerging molecular pathways related to the observed DNA methylation changes in WTC-exposed groups were explored and summarized. Results: WTC dust exposure appears to be associated with DNA methylation changes across the genome. Notably, WTC dust exposure appears to be associated with increased global DNA methylation; direct dysregulation of cancer genes and pathways, including inflammation and immune system dysregulation; and endocrine system disruption, as well as disruption of cholesterol homeostasis and lipid metabolism. Conclusion: WTC dust exposure appears to be associated with biologically meaningful DNA methylation changes, with implications for carcinogenesis and development of other chronic diseases.

Association of Personal Characteristics and Effectiveness of Immunotherapy in Late-Stage Non-Small Cell Lung Cancer: A Systematic Review.

BACKGROUND: Although immunotherapy can increase survival in non-small cell lung cancer (NSCLC), response rates are low. It is unclear which characteristics contribute to variability in immunotherapy efficacy and survival. Research is needed to identify reasons for heterogeneity in response rates to better tailor treatments. METHODS: Web of Science, Ovid EMBASE, and MEDLINE were queried from 2013 to January 2021, and all studies reporting overall or progression-free survival for patients treated with immunotherapy for NSCLC of at least stage IIIB were screened. RESULTS: Included were 18 randomized controlled trials (RCTs; 6534 immunotherapy RCTs; 11 192 nonimmunotherapy RCTs) and 16 observational studies (n = 9073 immunotherapy patients). Among RCTs, there was improved survival with the addition of immunotherapy in patients aged younger than 65 years in 10 of 17 studies; smokers in 8 of 15 studies; and males in 10 of 17 studies and 6 of 17 females. Only 5 studies reported outcomes by race. Among observational studies, younger patients (aged younger than 60, younger than 65, or younger than 70 years in most studies) had better survival than older patients (aged 60 years and older, 65 years and older, or 70 years and older) in 4 of 13 studies, ever-smokers in 7 of 13, and females in 2 of 14. Three studies reported race with mixed results. CONCLUSION: Although evidence is mixed, younger patients, smokers, and males may derive more benefit from immunotherapy. Evidence on racial differences is limited. Physicians should be mindful of personal characteristics when formulating treatment plans. Further research is needed to understand underlying mechanisms and to identify the best immunotherapy candidates and alternative treatments for those unlikely to benefit.

Interferon pathway lupus risk alleles modulate risk of death from acute COVID-19.

Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (756 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR = 29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in antiviral immunity.

Global DNA Methylation Profiles in Peripheral Blood of WTC-Exposed Community Members with Breast Cancer.

Breast cancer represents the most common cancer diagnosis among World Trade Center (WTC)-exposed community members, residents, and cleanup workers enrolled in the WTC Environmental Health Center (WTC EHC). The primary aims of this study were (1) to compare blood DNA methylation profiles of WTC-exposed community members with breast cancer and WTC-unexposed pre-diagnostic breast cancer blood samples, and (2) to compare the DNA methylation differences among the WTC EHC breast cancer cases and WTC-exposed cancer-free controls. Gene pathway enrichment analyses were further conducted. There were significant differences in DNA methylation between WTC-exposed breast cancer cases and unexposed prediagnostic breast cancer cases. The top differentially methylated genes were Intraflagellar Transport 74 (IFT74), WD repeat-containing protein 90 (WDR90), and Oncomodulin (OCM), which are commonly upregulated in tumors. Probes associated with established tumor suppressor genes (ATM, BRCA1, PALB2, and TP53) were hypermethylated among WTC-exposed breast cancer cases compared to the unexposed group. When comparing WTC EHC breast cancer cases vs. cancer-free controls, there appeared to be global hypomethylation among WTC-exposed breast cancer cases compared to exposed controls. Functional pathway analysis revealed enrichment of several gene pathways in WTC-exposed breast cancer cases including endocytosis, proteoglycans in cancer, regulation of actin cytoskeleton, axon guidance, focal adhesion, calcium signaling, cGMP-PKG signaling, mTOR, Hippo, and oxytocin signaling. The results suggest potential epigenetic links between WTC exposure and breast cancer in local community members enrolled in the WTC EHC program.

Prognostic Value of the Tumor Immune Microenvironment for Early-stage, Non-Small Cell Lung Cancer.

INTRODUCTION: The role of specific immune cell types within the tumor immune microenvironment in non-small cell lung cancer survival is unclear. The potential of these immune cells to become predictive biomarkers of prognosis, and to define subpopulations who will benefit of additional treatment is urgently needed. METHODS: Stage I to IIIA non-small cell lung cancer patients who underwent surgical resection were queried from the Cancer Genome Atlas; RNAseq data as well as clinical information was extracted. Sample-specific scores for different immune cells were computed via xCell. The association between each cell type and survival was assessed with Cox regression, both unadjusted and adjusted for sex, stage, smoking status, and tumor purity. Models were stratified by lung adenocarcinoma and lung squamous cell carcinoma. RESULTS: There were 383 lung adenocarcinoma and 328 lung squamous cell carcinoma samples, and 161 (42%) and 124 (38%) deaths respectively. There was no association between any immune cell infiltrations and survival in the combined unadjusted Cox regression model. After adjustment, the presence of CD8+ cytotoxic T cells (adjusted hazard ratio [HRajd]: 0.84; 95% confidence interval [CI]: 0.71-0.99; P=0.03), CD4+ helper T cells (HRajd: 0.79; 95% CI: 0.66-0.95; P=0.01) and CD20+ B cells (HRajd: 0.80; 95% CI: 0.66-0.97; P=0.02) were significant predictors of decreased risk of death. CONCLUSIONS: This study shows that the adjustment for clinical characteristics is key when evaluating tumor immune infiltration and its association with cancer outcomes. Adjustment for confounding factors modified the prognostic significance of specific immune cell populations in early-stage surgically resected NSCLC cases; clinical attributes may have high relevance on immune infiltration composition.