Resistin-like Molecule α and Pulmonary Vascular Remodeling: A Multi-Strain Murine Model of Antigen and Urban Ambient Particulate Matter Co-Exposure.

Pulmonary hypertension (PH) has a high mortality and few treatment options. Adaptive immune mediators of PH in mice challenged with antigen/particulate matter (antigen/PM) has been the focus of our prior work. We identified key roles of type-2- and type-17 responses in C57BL/6 mice. Here, we focused on type-2-response-related cytokines, specifically resistin-like molecule (RELM)α, a critical mediator of hypoxia-induced PH. Because of strain differences in the immune responses to type 2 stimuli, we compared C57BL/6J and BALB/c mice. A model of intraperitoneal antigen sensitization with subsequent, intranasal challenges with antigen/PM (ovalbumin and urban ambient PM2.5) or saline was used in C57BL/6 and BALB/c wild-type or RELMα-/- mice. Vascular remodeling was assessed with histology; right ventricular (RV) pressure, RV weights and cytokines were quantified. Upon challenge with antigen/PM, both C57BL/6 and BALB/c mice developed pulmonary vascular remodeling; these changes were much more prominent in the C57BL/6 strain. Compared to wild-type mice, RELMα-/- had significantly reduced pulmonary vascular remodeling in BALB/c, but not in C57BL/6 mice. RV weights, RV IL-33 and RV IL-33-receptor were significantly increased in BALB/c wild-type mice, but not in BALB/c-RELMα-/- or in C57BL/6-wild-type or C57BL/6-RELMα-/- mice in response to antigen/PM2.5. RV systolic pressures (RVSP) were higher in BALB/c compared to C57BL/6J mice, and RELMα-/- mice were not different from their respective wild-type controls. The RELMα-/- animals demonstrated significantly decreased expression of RELMß and RELMγ, which makes these mice comparable to a situation where human RELMß levels would be significantly modified, as only humans have this single RELM molecule. In BALB/c mice, RELMα was a key contributor to pulmonary vascular remodeling, increase in RV weight and RV cytokine responses induced by exposure to antigen/PM2.5, highlighting the significance of the genetic background for the biological role of RELMα.

Variability of blood eosinophils in patients in a clinic for severe asthma.

BACKGROUND: Blood eosinophils are used to determine eligibility for agents targeting IL-5 in patients with uncontrolled asthma. However, little is known about the variability of blood eosinophil measures in these patients before treatment initiation. OBJECTIVE: To characterize variability and patterns of variability of blood eosinophil levels in a real-world clinic for severe asthmatics. METHODS: Retrospective review of blood eosinophils measured over a 5-year period in patients enrolled in an urban clinic. Repeated measures of blood eosinophil levels in individuals were evaluated, and cluster analysis was performed to characterize patients by eosinophil patterns. Clinical characteristics associated with eosinophil levels and patterns of variability were analysed. RESULTS: Patients treated in the Bellevue Hospital Asthma Clinic within a 3-month period were identified (n = 219). Blood eosinophil measures were obtained over the previous 5 years. Only 6% (n = 13) of patients had levels that were consistently above 300 cells/µL. Nearly 50% (n = 104) had eosinophil levels that traversed the threshold of 300 cells/µL. In contrast, 102 (46%) had levels that never reached the threshold of 300 cells/µL. Cluster analyses revealed three clusters with differing patterns of levels and variability. There was a suggestion of decreased clinical control and increased atopy in the cluster with the greatest variability in blood eosinophil measures. CONCLUSION: In an urban clinic for patients referred for uncontrolled asthma, blood measures of eosinophils were variable and showed differing patterns of variability. These data reinforce the need to perform repeated eosinophil blood measures for appropriate designation for therapeutic intervention.

Aberrant immune response with consequent vascular and connective tissue remodeling - causal to scleroderma and associated syndromes such as Raynaud phenomenon and other fibrosing syndromes?

PURPOSE OF REVIEW: Scleroderma and other autoimmune-induced connective tissue diseases are characterized by dysfunctions in the immune system, connective tissue and the vasculature. We are focusing on systemic sclerosis (SSc)-associated pulmonary hypertension, which remains a leading cause of death with only a 50-60% of 2-year survival rate. RECENT FINDINGS: Much research and translational efforts have been directed at understanding the immune response that causes SSc and the networked interactions with the connective tissue and the vasculature. One of the unexpected findings was that in some cases the pathogenic immune response in SSc resembles the immune response to helminth parasites. During coevolution, means of communication were developed which protect the host from over-colonization with parasites and which protect the parasite from excessive host responses. One explanation for the geographically clustered occurrence of SSc is that environmental exposures combined with genetic predisposition turn on triggers of molecular and cellular modules that were once initiated by parasites. SUMMARY: Future research is needed to further understand the parasite-derived signals that dampen the host response. Therapeutic helminth infection or treatment with parasite-derived response modifiers could be promising new management tools for autoimmune connective tissue diseases.

The effects of endocannabinoid receptor agonist anandamide and antagonist rimonabant on opioid analgesia and tolerance in rats.

The role of the cannabinoid (CB) system in the tolerance to analgesic effect of opioid remains obscure. The aim of the present study was to evaluate the effects of the endocannabinoid nonselective receptor agonist anandamide (AEA) and CB1 receptor antagonist rimonabant (SR141716) on morphine analgesia and tolerance in rats. Male Wistar albino rats weighing 215-230 g were used in these experiments. To constitute morphine analgesic tolerance, a 3-day cumulative dosing regimen was used. The analgesic effects of AEA (10 mg/kg), SR141716 (10 mg/kg), and morphine (5 mg/kg) were considered at 30-min intervals by tail flick (TF) and hot plate (HP) analgesia tests. The analgesic effects of the drugs were measured as TF and HP latencies in all groups for each rat and converted to %MPE. The data were analysed by analysis of variance followed by Tukey test. The findings suggested that AEA in combination with morphine produced a significant increase in expression of analgesic tolerance to morphine. Conversely, cannabinoid receptor antagonist SR141716 attenuated morphine analgesic tolerance. In addition, administration of AEA with morphine increased morphine analgesia. In conclusion, we observed that the cannabinoid receptor agonist anandamide and CB1 receptor antagonist SR141716 plays a significant role in the opioid analgesia and tolerance.

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.

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.

Role of new agents affecting NO/cGMP pathway on ovalbumin-sensitized guinea pig trachea.

Asthma is a chronic inflammatory disease in which cell components play important roles. We aimed to evaluate the effects of NO/cGMP cleavage at trachea preparations isolated from ovalbumin-sensitized guinea pigs in vitro. Trachea rings were exposed to 3-ethyl-3-(ethylaminoethyl)-1-hydroxy-2-oxo-1-triazene (NOC-12), (±)-(E)-4-ethyl-2-[(Z)-hydroxyimino]-5-nitro-3-hexen-1-yl-nicotinamide (NOR-4), 2-(2-methylpyridin-4-yl)methyl-4-(3,4,5-trimethoxyphenyl)-8-(pyrimidin-2-yl) methoxy-1,2-dihydro-1-oxo-2,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride (T-0156), and electrical field stimulation (EFS). cGMP levels in trachea tissues were also measured. The relaxation responses of NOC-12, NOR-4, T-0156, and EFS were significantly decreased at ovalbumin-sensitized group. Nitric oxide (NO) donors significantly decreased the relaxation responses in the presence of 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ). L-Nitro-Arginine Methyl Ester (L-NAME) significantly decreased the EFS relaxation responses in both groups (experimental group and control group), but this effect was reversed by L-Arginine addition. In the experimental group, cGMP levels after EFS, carbachol, NOC-12, NOR-4, and T-0156 exposure were significantly lower than control group. In both groups, cGMP levels after NO donors' exposure were significantly lower in the presence of ODQ and the cGMP levels after EFS + L-NAME were significantly lower than EFS alone. These results may show the increased formation of NO because of the increased iNOS activity in airway sensitization leading to the inhibition of cNOS resulting in the decrease of endogen NO and decrease of activation of guanylyl cyclase.

Characteristics of Women with Lung Adenocarcinoma in the World Trade Center Environmental Health Center.

The destruction of the World Trade Center towers on 11 September 2001 exposed local residents, workers, and individuals in the area (Survivors) to dust and fumes that included known and suspected carcinogens. Given the potential for inhalation of toxic substances and the long latency after exposure, the incidence of lung cancer is expected to increase in WTC-exposed individuals. We describe the characteristics of women WTC Survivors with lung adenocarcinoma who were enrolled in the WTC Environmental Health Center (WTC EHC) between May 2002 and July 2021. A total of 173 women in WTC EHC had a diagnosis of any type of lung cancer, representing 10% of all cancers in women. Most of the lung cancers (87%) were non-small cell carcinomas, with adenocarcinoma (77%) being the most common subtype. Nearly half (46%) of these patients were exposed to dust clouds on 11 September 2001. Race and ethnicity varied by smoking status, as follows: 44% of Asian women compared with 29% of non-Hispanic White women were never-smokers (p < 0.001). There was no significant difference between the pathologic characteristics of adenocarcinomas between never and ever smokers. We also summarize EGFR, ALK, KRAS, ROS-1 and BRAF mutation status stratified by smoking, race and ethnicity. The identification of a relatively high proportion of women never-smokers with lung cancer warrants further investigation into the role of WTC dust exposure.

Characteristics of Cancers in Community Members Exposed to the World Trade Center Disaster at a Young Age.

The destruction of the World Trade Center (WTC) towers on 11 September 2001 (9/11) released tons of dust and smoke into the atmosphere, exposing hundreds of thousands of community members (survivors) and responders to carcinogens. The WTC Environmental Health Center (WTC EHC) is a federally designated surveillance and treatment program for community members who were present in the New York City disaster area on 9/11 or during the months that followed. WTC EHC enrollment requires exposure to the WTC dust and fumes and a federally certifiable medical condition, which includes most solid and blood cancers. Several studies have described the prevalence and characteristics of cancers in responders and survivors exposed to the WTC dust and fumes as adults. Cancers in those exposed at a young age warrant specific investigation since environmental toxin exposure at a younger age may change cancer risk. We describe the characteristics of 269 cancer patients with 278 cancer diagnoses among WTC EHC enrollees who were young in age (aged 0 to 30) on 9/11. These include 215 patients with a solid tumor (79.9%) and 54 with a lymphoid and/or hematopoietic cancer (20.1%). Among them, 9 patients had a known second primary cancer. A total of 23 different types of cancer were identified, including cancer types rare for this age group. Many were diagnosed in individuals lacking traditional cancer-specific risk factors such as tobacco use. The current study is the first to report specifically on cancer characteristics of younger enrollees in the WTC EHC program.

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.

Molecular Clustering Analysis of Blood Biomarkers in World Trade Center Exposed Community Members with Persistent Lower Respiratory Symptoms.

The destruction of the World Trade Center (WTC) on September 11, 2001 (9/11) released large amounts of toxic dusts and fumes into the air that exposed many community members who lived and/or worked in the local area. Many community members, defined as WTC survivors by the federal government, developed lower respiratory symptoms (LRS). We previously reported the persistence of these symptoms in patients with normal spirometry despite treatment with inhaled corticosteroids and/or long-acting bronchodilators. This report expands upon our study of this group with the goal to identify molecular markers associated with exposure and heterogeneity in WTC survivors with LRS using a selected plasma biomarker approach. Samples from WTC survivors with LRS (n = 73, WTCS) and samples from healthy control participants of the NYU Bellevue Asthma Registry (NYUBAR, n = 55) were compared. WTCS provided information regarding WTC dust exposure intensity. Hierarchical clustering of the linear biomarker data identified two clusters within WTCS and two clusters within NYUBAR controls. Comparison of the WTCS clusters showed that one cluster had significantly increased levels of circulating matrix metalloproteinases (MMP1, 2, 3, 8, 12, 13), soluble inflammatory receptors (receptor for advanced glycation end-products-RAGE, Interleukin-1 receptor antagonist (IL-1RA), suppression of tumorigenicity (ST)2, triggering receptor expressed on myeloid cells (TREM)1, IL-6Ra, tumor necrosis factor (TNF)RI, TNFRII), and chemokines (IL-8, CC chemokine ligand- CCL17). Furthermore, this WTCS cluster was associated with WTC exposure variables, ash at work, and the participant category workers; but not with the exposure variable WTC dust cloud at 9/11. A comparison of WTC exposure categorial variables identified that chemokines (CCL17, CCL11), circulating receptors (RAGE, TREM1), MMPs (MMP3, MMP12), and vascular markers (Angiogenin, vascular cell adhesion molecule-VCAM1) significantly increased in the more exposed groups. Circulating biomarkers of remodeling and inflammation identified clusters within WTCS and were associated with WTC exposure.

Effects of cannabinoid agonists on sheep sphincter of oddi in vitro.

BACKGROUND/AIMS: According to recent studies, the endocannabinoid system plays an important role in both physiological and pathophysiological situations. The purpose of the present study was to investigate the effects of cannabinoid (CB) agonists on isolated sheep sphincter of Oddi (SO)in vitro. METHODS: The isolated sheep SO tissues were mounted in organ baths and tested for isometric tension and cyclic GMP levels (cGMP) in response to the non-selective CB receptor agonist WIN 55,212-2 and the potent CB1 receptor agonist methanandamide in the presence and absence of the selective CB1 antagonist SR 141716A, the selective CB2 antagonist SR 144528 and the nonspecific inhibitor of nitric oxide (NO) synthase L-NAME. RESULTS: CB agonists relaxed SO in a concentration-dependent manner. These relaxations did not reduce in the presence of SR 144528 but were significantly reduced by SR 141716A and L-NAME. Carbachol significantly increased the cGMP levels compared with the control group and both of the CB receptor agonists significantly increased the cGMP levels compared with the control and carbachol groups. On the other hand, L-NAME prevented the increase in cGMP levels caused by CB agonists. CONCLUSION: These results show that the relaxation by the agonists may be through CB1 receptors. The decrease of CB relaxation responses by L-NAME, a nonspecific inhibitor of NO synthase, and the increase of cGMP levels in the SO tissues by CB agonists which decreased by L-NAME show that the relaxation effects of these agonists may also partially be via increasing the NO synthesis or release.

The nitric oxide-cGMP signaling pathway plays a significant role in tolerance to the analgesic effect of morphine.

Although the phenomenon of opioid tolerance has been widely investigated, neither opioid nor nonopioid mechanisms are completely understood. The aim of the present study was to investigate the role of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway in the development of morphine-induced analgesia tolerance. The study was carried out on male Wistar albino rats (weighing 180-210 g; n = 126). To develop morphine tolerance, animals were given morphine (50 mg/kg; s.c.) once daily for 3 days. After the last dose of morphine was injected on day 4, morphine tolerance was evaluated. The analgesic effects of 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), BAY 41-2272, S-nitroso-N-acetylpenicillamine (SNAP), N(G)-nitro-L-arginine methyl ester (L-NAME), and morphine were considered at 15 or 30 min intervals (0, 15, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests (n = 6 in each study group). The results showed that YC-1 and BAY 41-2272, a NO-independent activator of soluble guanylate cyclase (sGC), significantly increased the development and expression of morphine tolerance, and L-NAME, a NO synthase (NOS) inhibitor, significantly decreased the development of morphine tolerance. In conclusion, these data demonstrate that the nitric oxide-cGMP signal pathway plays a pivotal role in developing tolerance to the analgesic effect of morphine.

Investigation of the cardiac effects of pancuronium, rocuronium, vecuronium, and mivacurium on the isolated rat atrium.

BACKGROUND: Pancuronium, vecuronium, rocuronium, and mivacurium are nondepolarizing neuromuscular blocking agents that affect the cardiovascular system with different potencies. Their cardiovascular effects are clinically significant in the anesthetic management of patients, particularly those undergoing cardiac surgery. OBJECTIVE: We aimed to compare the cardiac effects of these compounds, such as heart rate and developed force, in one species under identical experimental conditions in isolated rat atria. METHODS: The left or right atria of rats were removed and suspended in organ baths. Pancuronium, vecuronium, rocuronium, or mivacurium were added cumulatively (10(-9)-10(-5) M) in the presence and absence of the nonselective ß-blocker propranolol (10(-8) M) and the noradrenaline reuptake inhibitor desipramine (10(-7) M), and heart rate changes were recorded in spontaneously beating right atria. Left atrial preparations were stimulated by electrical field stimulation using a bipolar platinum electrode, and the effects of cumulative concentrations of these nondepolarizing neuromuscular blocking agents on the developed force in the presence and absence of propranolol (10(-8) M) and desipramine (10(-7) M) were recorded. RESULTS: Pancuronium increased heart rate in a dose-dependent manner compared with the control group (P < 0.027). Vecuronium, rocuronium, and mivacurium also increased heart rate in a dose-dependent manner, but the changes were not statistically significant. Although propranolol decreased the pancuronium heart rate effect (P < 0.05), it did not change the heart rate effects with vecuronium, rocuronium, or mivacurium. Desipramine did not change the heart rate effects of vecuronium, rocuronium, mivacurium, or pancuronium. All 4 drugs increased developed force in a dose-dependent manner; the increases were significant at 10(-5) M concentration for pancuronium and at 10(-6) and 10(-5) M concentrations for vecuronium, rocuronium, and mivacurium (P < 0.038). These increases in developed force were abolished with the addition of propranolol. Desipramine did not change the developed force effects of any of the 4 drugs. CONCLUSIONS: The heart rate effect of pancuronium and developed force effects of pancuronium, vecuronium, rocuronium, and mivacurium may occur via direct stimulation of ß receptors. Although our investigation was an in vitro study, the effects found may be important especially under pathologic conditions, such as hypertension, in which patients usually use ß-blocking agents, which cause ß receptor upregulation.

Lung Cancer Characteristics in the World Trade Center Environmental Health Center.

The destruction of the World Trade Center (WTC) towers on 11 September 2001 resulted in acute and chronic dust and fume exposures to community members, including local workers and residents, with well-described aerodigestive adverse health effects. This study aimed to characterize lung cancer in the WTC Environmental Health Center (WTC EHC) focusing on gender and smoking history. WTC EHC patients undergo an initial evaluation that includes WTC exposure information, demographics, and tobacco use. Detailed cancer characteristics are recorded from pathology reports. As of 31 December 2019, 248 WTC EHC patients had a diagnosis of lung cancer. More patients with lung cancer were women (57%) compared to men (43%). Many cases (47% women, 51% men) reported acute dust cloud exposure. Thirty-seven percent of lung cancer cases with available smoking history were never-smokers (≤1 pack-years) and 42% had a ≤5 pack-year history. The median age of cancer diagnosis in never-smoking women was 61 years compared to 66 years in men. Adenocarcinoma was more common in never-smokers compared to ever-smokers (72% vs. 65%) and in women compared to men (70% vs. 65%). We provide an initial description of lung cancers in local community members with documented exposure to the WTC dust and fumes.

Breast Cancer Characteristics in the Population of Survivors Participating in the World Trade Center Environmental Health Center Program 2002-2019.

The destruction of World Trade Center on 11 September 2001 exposed local community members to a complex mixture of known carcinogens and potentially carcinogenic substances. To date, breast cancer has not been characterized in detail in the WTC-exposed civilian populations. The cancer characteristics of breast cancer patients were derived from the newly developed Pan-Cancer Database at the WTC Environmental Health Center (WTC EHC). We used the Surveillance, Epidemiology, and End Results (SEER) Program breast cancer data as a reference source. Between May 2002 and 31 December 2019, 2840 persons were diagnosed with any type of cancer at the WTC EHC, including 601 patients with a primary breast cancer diagnosis (592 women and 9 men). There was a higher proportion of grade 3 (poorly differentiated) tumors (34%) among the WTC EHC female breast cancers compared to that of the SEER-18 data (25%). Compared to that of the SEER data, female breast cancers in the WTC EHC had a lower proportion of luminal A (88% and 65%, respectively), higher proportion of luminal B (13% and 15%, respectively), and HER-2-enriched (5.5% and 7%, respectively) subtypes. These findings suggest considerable differences in the breast cancer characteristics and distribution of breast cancer intrinsic subtypes in the WTC-exposed civilian population compared to that of the general population. This is important because of the known effect of molecular subtypes on breast cancer prognosis.